Avermectin derivatives

ABSTRACT

Provided is a compound represented by the general formula (I) or a salt thereof:  
                 
 
     wherein, —X Y— represents —CH═CH— and the like,   between R 2  and the carbon atom at 5-position represents a single bond or a double bond, R 1  represents a lower alkyl group, a formyl group, a carboxyl group, a lower alkoxycarbonyl group (wherein a lower alkyl moiety of said lower alkoxycarbonyl group may be substituted with a heterocyclic group) and the like, and R 1a  represents a hydrogen atom, provided when R 1  represents a lower alkoxycarbonyl group and the like, R 1a  may further represents a lower alkoxycarbonyl group and the like, when   between R 2  and the carbon atom at 5-position is a single bond, R 2  represents a hydroxyl group and the like, and when   between R 2  and the carbon atom at the 5-position is a double bound, R 2  combines with the carbon atom at 5-position to form a hydroxime group (—C(═NOH)) and the like, and R 3  represents a hydroxyl group or a tri(lower alkyl)silyloxy group.

TECHNICAL FIELD

[0001] The present invention relates to avermectin derivatives havingantiparasitic activity.

BACKGROUND ART

[0002] Avermectins are antiparasitic antibiotics produced byStreptomyces avermitilis. Four main ingredients (A1a, A2a, B1a and B2a)have been known, and among them, avermectin B1a is known to have potentactivity (Japanese Patent Unexamined Publication (KOKAI) No. (Hei)3-254678/1991).

[0003] Various derivatives have been synthesized so far to provideavermectin derivatives having higher activity. However, thesederivatives fail to have fully satisfactory antiparasitic activity.

DISCLOSURE OF THE INVENTION

[0004] An object of the present invention is to provide avermectinderivatives having antiparasitic activity.

[0005] In order to find avermectin derivatives having higherantiparasitic activity, the inventors of the present inventionsynthesized various derivatives using avermectin B1a, ivermectin oravermectin B2a as a starting material. As a result, they succeeded inobtaining derivatives represented by the following general formula (I)which have high antiparasitic activity. The present invention wasachieved on the basis of the findings.

[0006] The present invention thus provides compounds represented by thegeneral formula (I) or salts thereof:

[0007] wherein, —X

Y— represents —CH═CH—, —CH₂—C(═O)—, —CH₂—CH₂—, —CH₂—CH(R¹³)— (whereinR¹³ represents a hydroxyl group or a lower alkylcarbonyloxy group) or—CH₂—C(═N—OR^(13c))— (wherein R^(13c) represents a hydrogen atom or alower alkyl group),

between R² and the carbon atom at 5-position represents a single bond ora double bond,

[0008] R¹ represents a substituted or unsubstituted lower alkyl group, aformyl group, a carboxyl group, a lower alkoxycarbonyl group (wherein alower alkyl moiety of said lower alkoxycarbonyl group may be substitutedwith a heterocyclic group), —CH═N—OR⁴ (wherein R⁴ represents a hydrogenatom or a lower alkyl group), a lower alkenyloxycarbonyl group,—CH═N—NH—CONH₂, a cyano group, —COR⁵ (wherein R⁵ represents anarylalkyloxy group (wherein the aryl group may contain one or morehetero atoms as ring-constituting atoms) or —NR⁶R⁷ (wherein R⁶ and R⁷are combined together with the adjacent nitrogen atom to form anitrogen-containing heterocyclic group), a vinyl group substituted witha lower alkenyloxycarbonyl group, —CO—S—CH₂—CH₂—NH—CO—R^(x) (whereinR^(x) represents a lower alkyl group), —CH═CH—COOH, or a substituted orunsubstituted aryl group, and R^(1a) represents a hydrogen atom,provided that when R¹ represents a lower alkoxycarbonyl group (wherein alower alkyl moiety of said lower alkoxycarbonyl group may be substitutedwith a heterocyclic group) or a carboxyl group, R^(1a) may furtherrepresents a lower alkoxycarbonyl group (wherein a lower alkyl moiety ofsaid lower alkoxycarbonyl group may be substituted with a heterocyclicgroup), a carboxyl group, a cyano group, or an aryl group,

[0009] and provided that when —X

Y— is —CH₂—C(═O), —CH₂—CH₂—, or —CH₂—CH(R^(13d))— (wherein R^(13d)represents a lower alkylcarbonyloxy group), a substituent at the4″-position may be a hydroxyl group instead of OCHR¹R^(1a),

[0010] when

between R² and the carbon atom at 5-position is a single bond, R²represents a hydroxyl group, a lower alkoxyl group, or a tri(loweralkyl)silyloxy group, and when

between R² and the carbon atom at the 5-position is a double bound, R²is combined with the carbon atom at 5-position to form a carbonyl groupor a hydroxime group (—C(═NOH)), and

[0011] R³ represents a hydroxyl group or a tri(lower alkyl)silyloxygroup.

[0012] Among the compounds of the general formula (I) of the presentinvention, the compounds or salts thereof wherein R² is a hydroxyl groupare preferred. Also among the compounds of the general formula (I) ofthe present invention, the compounds or salts thereof wherein R² iscombined with the carbon atom at 5-position to form a hydroxime group(—C(═NOH)) are preferred.

[0013] Among the aforementioned compounds, the compounds or saltsthereof wherein R³ is a hydroxyl group are preferred.

[0014] According to another aspect of the present invention, providedare medicaments which comprise as an active ingredient the compoundrepresented by the aforementioned general formula (I) or aphysiologically acceptable salt thereof. The medicaments can beadministered as antiparasitics to a mammal including a human.

[0015] According to further aspects of the present invention, providedare use of the compound represented by the aforementioned generalformula (I) or the physiologically acceptable salt thereof for themanufacture of the aforementioned medicament; and a method fortherapeutic treatment of parasitosis which comprises the step ofadministering a therapeutically effective amount of the compoundrepresented by the aforementioned general formula (I) or aphysiologically acceptable salt thereof to a mammal including a human.

[0016] Hereinafter the compounds represented by the general formula (I)may be referred to as the compounds (I).

[0017] In the definition of each group in the compounds (I), the loweralkyl group may be any of C₁-C₈ linear, branched, and cyclic alkylgroups or a combination thereof, preferably a C₁-C₈ linear or branchedalkyl group. The lower alkyl group includes, for example, a methylgroup, ethyl group, propyl group, isopropyl group, cyclopropyl group,butyl group, isobutyl group, sec-butyl group, tert-butyl group,cyclopropylmethyl group, cyclobutyl group, pentyl group, hexyl group,heptyl group, and octyl group. A lower alkyl moiety in functional groupshaving the lower alkyl moiety, e.g., a lower alkoxyl group, a loweralkylcarbonyloxy group, a lower alkoxycarbonyl group, and a tri(loweralkyl)silyloxy group, has the same meaning as that defined in theaforementioned lower alkyl group, unless otherwise specificallymentioned. The lower alkyl moieties of the tri(lower alkyl)silyloxygroup may be the same or different. The alkylene moiety of thearylalkyloxy group represented by R⁵ is preferably a group formed byeliminating one hydrogen atom from the aforementioned lower alkyl group.

[0018] Examples of a lower alkenyl moiety in the loweralkenyloxycarbonyl group include C₂-C₆ straight and branched alkenylgroups, for example, a vinyl group, allyl group, methacryl group,butenyl group, pentenyl group, hexenyl group and the like. The number ofdouble bonds present in the alkenyl group is not particularly limited,and preferably one.

[0019] The heterocyclic group may be either an aromatic or aliphaticheterocyclic group. Examples of the aromatic heterocyclic group include,for example, a 5- or 6-membered monocyclic aromatic heterocyclic groupwhich contains at least one heteroatom selected from the groupconsisting of nitrogen, oxygen, and sulfur atoms. More specifically,examples include a pyridyl group, pyrrolyl group, furyl group, thienylgroup, thiazolyl group, pyrazinyl group, imidazolyl group, pyrazolylgroup, triazolyl group, tetrazolyl group, and oxazolyl group. Examplesof the aliphatic heterocyclic group include, for example, a 5- or6-membered monocyclic aliphatic heterocyclic group which contains atleast one heteroatom selected from the group consisting of nitrogen,oxygen, and sulfur atoms. More specifically, examples include apyrrolidinyl group, tetrahydrofuryl group, and tetrahydropyranyl group.

[0020] The nitrogen-containing heterocyclic group formed together withthe adjacent nitrogen atom includes a morpholino group, thiomorpholinogroup, piperidino group, 1-piperazinyl group, and 1-pyrrolidinyl group.Among them, a morpholino group, and piperidino group are preferred.

[0021] Examples of the aryl group include, for example, a phenyl group,naphthyl group, and the like. Examples of the aryl moiety of thearylalkyloxy group represented by R⁵ include the same examples as thosementioned above. Examples of the arylalkyloxy group containing one ormore hetero atoms represented by R⁵ include those wherein the arylmoiety is a 5- or 6-membered monocyclic aromatic heterocyclic groupwhich contains at least one heteroatom selected from the groupconsisting of nitrogen, oxygen, and sulfur atoms. More specifically,examples of the aryl moiety include, for example, a pyridyl group,pyrrolyl group, furyl group, thienyl group, thiazolyl group, pyrazinylgroup, imidazolyl group, pyrazolyl group, triazolyl group, tetrazolylgroup, and oxazolyl group. Among them, a furyl group is preferred.

[0022] The type and number of the substituent of the substituted loweralkyl group are not particularly limited. Preferably, examples includefrom 1 to 3 substituents such as a hydroxyl group, a halogen atom (“ahalogen atom” used herein may be any of fluorine, chlorine, bromine, andiodine atoms), an amino group, a mono(lower alkyl)amino group, a (loweralkanoyl)amino group, an aryl group, a monocyclic aromatic heterocyclicgroup such as those exemplified above, a lower alkanoyloxy group, anazide group, a substituted or unsubstituted arylsulfonyloxy group (thesubstituent of the substituted aryisulfonyloxy group is a lower alkylgroup having the same meaning as that defined above), a loweralkylsulfonyloxy group, hydroxyamino group, a mono(lower alkoxy)aminogroup, a heterocyclic group (examples thereof include those groupsexemplified for the aforementioned heterocyclic group and thenitrogen-containing heterocyclic group formed together with the adjacentnitrogen atom), a heterocyclic carbonyloxy group (i.e.,heterocycle-C(═O)—O— wherein the heterocyclic moiety has the samemeaning as that defined in the aforementioned heterocyclic group and theheterocyclic moiety may be substituted with a halogen atom (which hasthe same meaning as that defined above) or a lower alkoxycarbonylgroup), a heterocyclic oxy group such as tetrahydropyranyloxy group, acarboxyl group, a lower alkoxycarbonyl group, and a cyano group (inthese groups, each alkyl moiety of the mono(lower alkoxy)amino group,lower alkoxycarbonyl group, lower alkylsulfonyloxy group, mono(loweralkyl)amino group, lower alkanoylamino group and lower alkanoyloxy grouphas the same meaning as that defined in the aforementioned lower alkylgroup, and the aryl group and aryl moieties of the arylsulfonyloxy grouphave the same meaning as that defined in the aforementioned aryl group).

[0023] More specifically, examples of the substituted lower alkyl groupinclude a hydroxymethyl group, bromomethyl group, iodomethyl group,azidomethyl group, aminomethyl group, p-toluenesulfonyloxymethyl group,and the like. Further, when the substituted lower alkyl group has two ormore of substituents, for example, examples of the two of substituentson the lower alkyl group include two lower alkoxycarbonyl groups (theselower alkoxycarbonyl groups have the same meaning as that definedabove), two carboxyl groups, carboxyl group and cyano group, carboxylgroup and an aryl group (this aryl group has the same meaning as theaforementioned aryl group). When the substituted lower alkyl group hastwo of substituents, methyl group is preferred as the lower alkyl group.

[0024] The type and number of the substituent of the substituted arylgroup are not particularly limited. Preferably, the number of thesubstituent is from 1 to 5, and examples include nitro group, aminogroup, hydroxyl group and a halogen atom.

[0025] Salts of the compounds (I) are not particularly limited, andphysiologically acceptable salts are preferred. Examples of the saltsinclude acid-addition salts, metal salts, ammonium salts, and organicamine-addition salts. Examples of the acid-addition salts includeinorganic acid salts such as hydrochlorides, sulfates, nitrates, andphosphates, and organic acid salts such as acetates, maleates,fumarates, and citrates. Examples of the metal salts include alkalimetal salts such as sodium salts and potassium salts, alkaline-earthmetal salts such as magnesium salts and calcium salts, aluminium salts,and zinc salts. Examples of the ammonium salts include ammonium saltsand tetramethylammonium salts, and examples of the organicamine-addition salts include salts with morpholine and piperidine. Whena salt of the compound (I) is used as an active ingredient of themedicament of the present invention, a physiologically acceptable saltis preferably used.

[0026] Preparations of the compounds (I) will be explained below.

[0027] Avermectin B1a, which is used as a starting material for theavermectin derivatives disclosed in the present invention, is isolatedfrom the culture of Streptomyces avermitilis, and is a known compound(Japanese Patent Unexamined Publication No. (Hei) 3-74397/1991 and3-254678/1991, and U.S. Pat. No. 5,206,155, and the like).

[0028] In the present invention, 5-O-tri(lower alkyl)silyl-7-O-tri(loweralkyl)silylayermectin B1a, which is used as an intermediate for thesynthesis of compounds (I), can be synthesized by using avermectin B1aas a starting material according to the method described in Journal ofMedicinal Chemistry (J. Med. Chem.), vol. 25, 658-663 (1982) or asimilar method thereto.

[0029] Specifically, the compound can be prepared by tri(loweralkyl)silylating the 5-hydroxyl group of avermectin B1a, and thentri(lower alkyl)silylating the 7-hydroxyl group of the same.

[0030] In the present invention, 5-O-tri(lower alkyl)silyl-7-O-tri(loweralkyl)silylivermectin, which is used as an intermediate for thesynthesis of compounds (I), can be prepared by tri(loweralkyl)silylating the 5-hydroxyl group of ivermectin, and then tri(loweralkyl)silylating the 7-hydroxyl group of the same.

[0031] In the present invention, 5-O-tri(lower alkyl)silyl-7-O-tri(loweralkyl)silylayermectin B2a, which is used as an intermediate for thesynthesis of compounds (I), can be prepared by tri(loweralkyl)silylating the 5-hydroxyl group of avermectin B2a, and thentri(lower alkyl)silylating the 7-hydroxyl group of the same.

[0032] In the following preparations, when a defined group is changedunder conditions for a method to be applied, or the group is unsuitablefor carrying out the method, desired compounds can be obtained byemploying introduction and elimination of a protective groupconventionally used in synthetic organic chemistry [see, for example,Protective Groups in Organic Synthesis, T. W. Greene, John Wiley & SonsInc. (1981)].

[0033] In compounds (I) obtained in Preparations 1 to 8 mentioned below,

between R² and the carbon atom at the 5-position represents a singlebond, R² represents a tri(lower alkyl)silyloxy group, and R³ representsa tri(lower alkyl)silyloxy group.

[0034] Preparation 1

[0035] The compound (I) wherein R¹ is a lower alkoxycarbonyl group canbe prepared by reacting 5-O-tri(lower alkyl)silyl-7-O-tri(loweralkyl)silylayermectin B1a with an alkyl diazoacetate derivative such asethyl diazoacetate. The compound (I) wherein R¹ is a carboxyl group canbe prepared by treating the above compound with a base such as alcoholicpotassium hydroxide.

[0036] Preparation 2

[0037] The compound (I) wherein R¹ is —CON(R⁶)(R⁷) (wherein R⁶ and R⁷combine together with the adjacent nitrogen atom to form anitrogen-containing heterocyclic group) can be prepared by reacting thecompound (I) wherein R¹ is a carboxyl group obtained in Preparation 1with a cyclic amine compound (piperazine, morpholine and the like) inthe presence of a condensing agent. Examples of the condensing agentinclude 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSCI)hydrochloride, 1,3-dicyclohexylcarbodiimide and the like.

[0038] Further, the compound (I) wherein R¹ is —COR^(5a) (wherein R^(5a)represents an arylalkyloxy group wherein the aryl group may contain oneor more hetero atoms as ring-constituting atoms) can be prepared byreacting the compound (I) wherein R¹ is a carboxyl group with anarylalkyl alcohol (the aryl group may contain one or more hetero atomsas ring-constituting atoms) in the presence of a condensing agent.

[0039] Preparation 3

[0040] The compound (I) wherein R¹ is a formyl group can be prepared byreducing the compound (I) wherein R¹ is a carboxyl group or a loweralkoxycarbonyl group obtained in Preparation 1. As the reducing agent,sodium borohydride, lithium aluminum hydride, diisobutyl aluminumhydride or the like is used. By reacting the resulting aldehyde compoundwith a compound represented as H₂N—OR⁴ (R⁴ has the same meaning as thatdefined above), the compound can be converted into an oxime compound(hydroxime compound or alkoxime compound).

[0041] The compound (I) wherein R¹ is a hydroxymethyl group can beprepared by treating the compound (I) wherein R¹ is a carboxyl group ora lower alkoxycarbonyl group obtained in Preparation 1 with a morepotent reducing agent. As such a reducing agent, lithiumtriethylborohydride (super hydride), and the like can be used.

[0042] Preparation 4

[0043] The compound (I) wherein R¹ is a substituted or unsubstitutedaryl group can be prepared by reacting 5-O-tri(loweralkyl)silyl-7-O-tri(lower alkyl)silylayermectin B1a with a substitutedor unsubstituted aryl halide (the substituent on the aryl group has thesame meaning as that of the substituent of the aforementionedsubstituted aryl group, and the halide has the same meaning as that ofthe aforementioned halogen). For example, by reacting p-nitrobenzylbromide as the substituted aryl halide, the compound (I) wherein R¹ isp-nitrophenyl group can be prepared. By reducing the resulting compound,the compound wherein R¹ is p-aminophenyl group can be prepared. Thereduction is performed as catalytic reduction in the presence of, forexample, palladium carbon catalyst. Further, the compound (I) wherein R¹is p-nitrophenyl group can be subjected to deprotection reaction of the5-position and 7-position (deprotection is performed according toPreparation 9 mentioned below), and then a reduction reaction to preparethe compound (I) wherein R¹ is p-aminophenyl group and wherein hydroxygroups are substituted at the 5-position and 7-position.

[0044] Preparation 5

[0045] By using the compound (I) wherein R¹ is a hydroxymethyl group asa starting material, another compound (I) can be prepared.

[0046] By reacting the compound (I) wherein R¹ is a hydroxymethyl groupwith a substituted or unsubstituted arylsulfonyl chloride or the like inthe presence of a base, the compound (I) wherein R¹ is a substituted orunsubstituted arylsulfonyloxymethyl group can be prepared.

[0047] By halogenating the hydroxyl group of the compound (I) wherein R¹is a hydroxymethyl group, the compound (I) wherein R¹ is a halogenatedmethyl group can be prepared. Examples of the halogenation conditionsinclude a reaction with triphenylphosphine/carbon tetrabromide in thepresence of a base, reaction with triphenylphosphine/iodine in thepresence of a base and the like.

[0048] By azidating the compound (I) wherein R¹ is a halogenated methylgroup, the compound (I) wherein R¹ is azidomethyl group can be prepared.Examples of the azidation conditions include a reaction with an alkaliazide such as sodium azide and potassium azide in a polar solvent andthe like.

[0049] By reducing the compound (I) wherein R¹ is an azidomethyl group,the compound (I) wherein R¹ is an aminomethyl group can be prepared.Examples of the reduction conditions include those used for conventionalmethods such as reduction with a reduction catalyst in the presence of asource of hydrogen such as hydrogen gas and hydrazine, reduction withtriphenylphosphine and the like.

[0050] By lower alkanoylating the compound (I) wherein R¹ is aminomethylgroup, the compound (I) wherein R¹ is a lower alkanoylaminomethyl groupcan be prepared. Examples of the lower alkanoylation method include amethod of reacting the compound (I) wherein R¹ is aminomethyl group witha lower alkanoyl halide, a method of reacting the compound (I) whereinR¹ is aminomethyl group with an acid anhydride, and the like.

[0051] By reacting the compound (I) wherein R¹ is a halogenated methylgroup with HNR⁶R⁷ (R⁶ and R⁷ have the same meanings as those definedabove), if necessary, in the presence of a base, the compound (I)wherein R¹ is —CH₂NR⁶R⁷ (R⁶ and R⁷ have the same meanings as thosedefined above) can be prepared.

[0052] Preparation 6

[0053] By reacting 5-O-tri(lower alkyl)silyl-7-O-tri(loweralkyl)silylayermectin B1a with an alkyl diazoacetate derivative having asubstituent such as diethyl diazomalonate, ethyl diazophenylacetate, andethyl diazocyanoacetate, the compound (I) wherein R¹ is a loweralkoxycarbonyl group, and R^(1a) is a lower alkoxycarbonyl group (thelower alkyl moiety of the lower alkoxycarbonyl group may be substitutedwith a heterocyclic group), a cyano group or an aryl group can beprepared.

[0054] The substituent at the 4″-position of the compound (I) obtainedabove wherein R¹ is a lower alkoxycarbonyl group, and R^(1a) is a loweralkoxycarbonyl group (the lower alkyl moiety of the lower alkoxycarbonylgroup may be substituted with a heterocyclic group), a cyano group or anaryl group can be converted, for example, as follows.

[0055] The compound wherein R¹ and R^(1a) are lower alkoxycarbonylgroups, the compound wherein R¹ is a lower alkoxycarbonyl group, andR^(1a) is a cyano group, or the compound wherein R¹ is a loweralkoxycarbonyl group, and R^(1a) is an aryl group can be treated under ahydrolysis condition (treatment with a base such as alcoholic potassiumhydroxide etc.) to prepare the compound wherein R¹ and R^(1a) arecarboxyl groups, the compound wherein R¹ is a carboxyl group, and R^(1a)is a cyano group, and the compound wherein R¹ is a carboxyl group, andR^(1a) is an aryl group.

[0056] By using a diazonium salt having different lower alkyl moietiesin two of the ester group moieties (e.g., diazonium salt prepared fromtert-butyl ethyl malonate ((H₃C)₃COOC—CH₂—COOCH₂—CH₃)) in thepreparation of the compound (I) wherein R¹ and R^(1a) are loweralkoxycarbonyl groups, the compound (I) wherein R1 and Rla are differentlower alkoxycarbonyl groups can be prepared. By performing selectivedeprotection of the ester groups, the compound (I) wherein one of R¹ andR^(1a) is a carboxyl group, and the other is a lower alkoxycarbonylgroup can also be prepared.

[0057] The aforementioned hydrolysis reaction at the 4″-position canalso be performed for the compound of which 5-position and/or 7-positionis deprotected, which can be obtained by deprotection of the 5-positionand/or 7-position (Preparation 9 mentioned below).

[0058] Preparation 7

[0059] 5-O-Tri(lower alkyl)silyl-7-O-tri(lower alkyl)silylayermectin B1awherein R¹ is a lower alkenyloxycarbonyl group and 5-O-tri(loweralkyl)silyl-7-O-tri(lower alkyl)silylayermectin B1a wherein R¹ is acyano group can be produced according to Preparation 1.

[0060] 5-O-Tri(lower alkyl)silyl-7-O-tri(lower alkyl)silylayermectin B1awherein R¹ is —CH═N—NH—CONH₂ can be prepared from 5-O-tri(loweralkyl)silyl-7-O-tri(lower alkyl)silylayermectin B1a wherein R¹ is aformyl group and H₂N—NH—CONH₂ or a salt thereof (acid addition saltetc.).

[0061] 5-O-Tri(lower alkyl)silyl-7-O-tri(lower alkyl)silylayermectin B1awherein R¹ is a vinyl group substituted with a lower alkenyloxycarbonylgroup can be prepared by reacting 5-O-tri(loweralkyl)silyl-7-O-tri(lower alkyl)silylayermectin B1a wherein R¹ is aformyl group with a suitable Wittig reagent (e.g., Wittig reagentprepared from allyl diethylphosphonoacetate) or the like.

[0062] 5-O-Tri(lower alkyl)silyl-7-O-tri(lower alkyl)silylayermectin B1awherein R¹ is —CO—S—CH₂—CH₂—NH—CO—R^(x) (R^(x) has the same meaning asthat defined above) can be prepared by reacting 5-O-Tri(loweralkyl)silyl-7-O-tri(lower alkyl)silylayermectin B1a wherein R¹ is acarboxyl group with HS—CH₂—CH₂—NH—CO—R^(x) (R^(x) has the same meaningas that defined above).

[0063] 5-O-Tri(lower alkyl)silyl-7-O-tri(lower alkyl)silylayermectin B1awherein R¹ is —CH═CH—COOH can be prepared by treating 5-O-tri(loweralkyl)silyl-7-O-tri(lower alkyl)silylayermectin B1a wherein R¹ is avinyl group substituted with a lower alkenyloxycarbonyl group under asuitable deprotection condition (deprotection with acid, deprotectionwith a hydrogen source such as sodium borohydride, hydrogen or hydrazinein the presence of a metal catalyst such astetrakistriphenylphosphonopalladium).

[0064] Preparation 8

[0065] The compound (I) wherein —X

Y— is —CH₂—C(═O)—, —CH₂—CH₂— or —CH₂—CH(R¹³)—(R¹³ has the same meaningas that defined above) can also be prepared by performing a reactionsimilar to those of Preparations 1 to 7 mentioned above using a suitablestarting material.

[0066] Among the compounds (I) mentioned above, the compound (2) wherein—X

Y— is —CH₂—C(═O)— can be prepared by performing a reaction similar tothose of Preparations 1 to 7 mentioned above using, as a startingmaterial, a compound obtained by tri(lower alkyl)silylating the5-hydroxyl group of avermectin B2a wherein a moiety corresponding to —X

Y— is —CH₂—CH(—OH)— (following formula) used as a starting material,performing a selective oxidation reaction for the 23-hydroxy group andthen tri(lower alkyl)silylating the 7-hydroxyl group.

[0067] Among the compounds (I) mentioned above, the compound (I) wherein—X

Y— is —CH₂—CH₂— can be prepared by performing a reaction similar tothose of Preparation 1 to 7 mentioned above using 5-O-tri(loweralkyl)silyl-7-O-tri(loweralkyl)-silylivermection obtained in thereference examples or the like as a starting material.

[0068] Among the compounds (I) mentioned above, the compound (I) wherein—X

Y— is —CH₂—C(R^(13a))— (wherein R^(13a) represents a hydroxyl group) canbe prepared by performing a reaction similar to those of Preparations 1to 7 mentioned above using, as a starting material, a compound obtainedby tri(lower alkyl)silylating the 5-hydroxyl group of avermectin B2awherein a moiety corresponding to —X

Y— is —CH₂—CH(—OH)— (formula mentioned above) used as a startingmaterial, and tri(lower alkyl)silylating the 7-hydroxyl group.

[0069] Further, among the compounds (I) mentioned above, the compound(I) wherein —X

Y— is —CH₂—C(R^(13b))— (wherein R^(13b) represents a loweralkylcarbonyloxy group having the same meaning as that defined above)can be prepared by performing a reaction similar to those ofPreparations 1 to 7 mentioned above using, as a starting material, acompound obtained by tri(lower alkyl)silylating the 5-hydroxyl group ofavermectin B2a wherein a moiety corresponding to —X

Y— is —CH₂—CH(—OH)— (formula mentioned above) used as a startingmaterial, lower alkanoylating the 23-hydroxyl group and then tri(loweralkyl)silylating the 7-hydroxyl group.

[0070] The compound (I) wherein —X

Y— is —CH₂—C(═NOR^(13c))— (wherein R¹³c represents a hydrogen atom or alower alkyl group) can be prepared by reacting the 23-carbonyl group ofthe compound (I) wherein —X

Y— is —CH₂—C(═O)— used as a starting material with H₂N—OR^(13c) (whereinR^(13c) has the same meaning as that defined above) in the same manneras in Preparation 3. By further performing a reaction similar to thoseof Preparations 1 to 7 mentioned above, various compounds (I) wherein —X

Y— is —CH₂—C(═N—OR^(13c))— (wherein R^(13c) has the same meaning as thatdefined above) can be prepared.

[0071] Preparation 9

[0072] By performing deprotection of the 5-position and/or 7-position ofthe compounds (I) obtained in Preparation 1 to 8, the compounds (I)wherein R² and/or R³ are/is a hydroxyl group can be obtained. Forexample, by treating the compounds obtained in Preparation 1 to 8 with adesilylating agent in a catalytic amount to an amount as a solvent in aninert solvent at a temperature of −78° C. to the boiling point of thesolvent used for 1 minute to 24 hours, deprotected compounds can beobtained. As the inert solvent, tetrahydrofuran, diethyl ether, benzene,toluene, pyridine, isopropyl acetate, and the like can be used alone orin combination. Examples of the desilylating agent include hydrogenfluoride, hydrochloric acid, hydrogen bromide, sulfuric acid, hydrogenfluoride/pyridine complex and the like.

[0073] The tri(lower alkyl)silyloxy group of at the 5-position and/or7-position may be converted into a hydroxyl group depending on thereaction conditions at the time of conversion of functional groups inother positions.

[0074] Preparation 10

[0075] When R² is a hydroxyl group, by oxidizing the hydroxyl group in aconventional manner, the compound (I) wherein R² and the carbon atom ofthe 5-position together form a carbonyl group can be prepared.

[0076] Furthermore, by reacting the resulting compound (I), wherein R²and the carbon atom of the 5-position combine together to form acarbonyl group, with hydroxylamine or a salt thereof (e.g., an acidaddition salt such as hydrochloride) in a conventional manner, thecompound (I) wherein R² and the carbon atom of the 5-position combinetogether to form a hydroxime group {—C(═NOH)} can also be prepared.

[0077] The aforementioned methods are shown as typical examples of thepreparations of the compounds (I), and therefore, the preparations ofthe compounds (I) are not limited to those explained above. It can beeasily understood by a person skilled in the art that the compounds ofthe present invention can be prepared by other methods and the compounds(I) can also be obtained by carrying out the above methods in anappropriate combination or with an appropriate modification oralteration, if necessary.

[0078] In addition, the compounds (I) can also be obtained by anappropriate combination of the methods for converting a functional groupwhich are usually used in the field of synthetic organic chemistry. Forexample, the compound (I) wherein R² is a methoxy group can be preparedby a conventional methylation of the hydroxyl group of the correspondingcompound wherein R² is a hydroxyl group. Similarly, the compound (I)wherein R² is another lower alkoxyl group can be prepared by loweralkylation of the corresponding compound wherein R² is hydroxyl group.

[0079] For converting functional groups, desired conversions offunctional groups can efficiently be made by protecting appropriatefunctional groups by methods for protection and deprotectionconventionally used in the field of synthetic organic chemistry [forexample, see Protective Groups in Organic Synthesis, T. W. Greene, JohnWiley & Sons Inc. (1981)], if necessary.

[0080] Specific examples of the aforementioned preparation and otherpreparations are described in Examples, and accordingly, a personskilled in the art can prepare any compounds falling within the compound(I) by referring to the above general explanations and specificexplanations in Examples, and by appropriately choosing startingmaterials, reagents and reaction conditions and by applying anappropriate alteration or modification, if necessary.

[0081] Purification of the desired compounds in the aforementionedpreparations can be made by an appropriate combination of methodsordinarily used in the filed of synthetic organic chemistry, forexample, filtration, extraction, washing, drying, concentration,crystallization, and various chromatography techniques and the like.Synthetic intermediates may be subjected to a next reaction withoutpurification.

[0082] Isomers such as positional isomers, geometrical isomers,tautomers, and optical isomers may exist as the compounds (I). Anypossible isomers and mixtures thereof in any proportion fall within thescope of the present invention. In the specification, when a bond of afunctional group that substitutes on a carbon atom forming a double bondis represented by a waved line, the compound means an E- or Z-compound,or a mixture thereof.

[0083] For the preparation of a salt of the compound (I), when thecompound (I) is obtained in the form of a salt, the resulting salt, perse, may be purified. When a product is obtained in a free form, a saltmay be isolated and purified after dissolving or suspending the productin a suitable solvent, and adding an acid or a base thereto to form asalt. The compounds (I) and salts thereof may exist in the forms ofadducts with water or various solvents (i.e., hydrates or solvates), andthese adducts also fall into the scope of the present invention.Moreover, any forms of crystal also fall into the scope of the presentinvention.

[0084] Specific examples of the compounds (I) obtained according to thepresent invention are shown in Tables 1 to 4. However, the compounds ofthe present invention are not limited to these examples. In the tables,OTBDMS represents tert-butyldimethylsilyloxy (OSi(CH₃)₂C(CH₃)₃), andOTMS represents trimethylsilyloxy (OSi(CH₃)₃). TABLE 1

Compound No. R¹ R² R³ 1 CO₂CH₂CH₃ OTBDMS OTMS 2 CO₂CH₂CH₃ OH OH 3

OTBDMS OTMS 4

OH OH 5

OH OH 6 CO₂H OTBDMS OTMS 7 CO₂H OH OH 8 CHO OTBDMS OTMS 9 CH═N˜OH OH OH10

OH OH 11

OH OH 12 CH═N˜OCH₃ OH OH 13

OH OH 14 CH₂OH OTBDMS OTMS 15 CH₂OH OH OH 16

OTBDMS OTMS 17

OH OH 18 CH₂Br OTBDMS OTMS 19 CH₂N₃ OTBDMS OTMS 20 CH₂N₃ OH OH 21 CH₂NH₂OTBDMS OTMS 22 CH₂NH₂ OH OH 23 CH₂Br OH OH 24 CH₂l OTBDMS OTMS 25 CH₂lOH OH 26 CH₂NHCOCH₃ OH OH 27

OH OH 28

OH OH 29

OH OH

[0085] TABLE 2

Compound No. R¹ R^(1a) R² R³ 30 CO₂CH₂CH₃ CO₂CH₂CH₃ OTBDMS OTMS 31CO₂CH₂CH₃ CO₂CH₂CH₃ OH OH 32 CO₂H CN OH OH 33 CO₂H CO₂H OH OH 34 CO₂HC₆H₅ OH OH

[0086] TABLE 3

Compound No. R¹ R² R³ 35 CO₂CH₂CH₃ OTBDMS OTMS 36 CO₂CH₂CH₃ OH OH 37CH₂OH OTBDMS OTMS 38 CH₂Br OTBDMS OTMS 39 CO₂H OH OH 40 CH₂OH OH OH 41CH₂Br OH OH

[0087] TABLE 4

Compound No. R¹ R² R³

42 CO₂CH₂CH₃ OTBDMS OTMS CH₂—CH(α—OH)— 43 CO₂CH₂CH₃ OH OH CH₂—CH(α—OH)—44 CO₂CH₂CH₃ OTBDMS OTMS CH₂—(C═O)— 45 CO₂CH₂CH₃ OH OH CH₂—(C═O)— 46CO₂CH₂CH₃ OTBDMS OTMS CH₂—(C═N˜OCH₃)— 47 CO₂CH₂CH₃ OH OH CH₂—(C═N˜OCH₃)—

[0088] As the active ingredient of the medicament of the presentinvention, one or more substances selected from the group consisting ofthe compounds represented by the general formula (I) in the free formand physiologically acceptable salts thereof, and hydrates thereof andsolvates thereof can be used. Any mixture of isomers or an isomer in apure form may be used. The medicament of the present invention isgenerally provided in the form of a pharmaceutical composition whichcomprises one or more pharmaceutical additives and the aforementionedsubstance as an active ingredient. A route of administration is notparticularly limited, and the medicament can be orally administeredusing preparations such as tablets, granules, capsules, syrups andpowders, or parenterally administered by means of injection, intrarectaladministration, transdermal administration or the like. Pharmaceuticalformulations suitable for oral or parenteral administration arewell-known to those skilled in the art, and they can appropriatelychoose pharmaceutical additives suitable for the manufacture of thepharmaceutical formulations.

[0089] The medicament of the present invention may be applied to variousparasitic diseases, and the kinds of the parasitic disease are notparticularly limited. The medicament of the present invention may beapplied to a human or a mammal other than a human. When the medicamentis applied to a mammal other than a human, the medicament may beadministered as a pharmaceutical composition, or alternatively, apharmaceutical composition or the aforementioned active ingredient, perse, may be added to a feed.

BEST MODE FOR CARRYING OUT THE INVENTION

[0090] The present invention will be explained more specifically withreference to examples. However, the present invention is not limited tothese examples.

[0091] Analytical data of the compounds described in the examples weremeasured by using the following apparatuses. The number and structure ofthe compounds are the same as those described in Table 1 to 4 set outabove.

[0092] IR: Horiba FT-210

[0093] NMR: JEOL (Nippon Denshi) JMN-EX270

[0094] MS: JEOL (Nippon Denshi) JMS-AX505

[0095] Solution A used in the following examples is a solution which isobtained by mixing 10 ml of hydrogen fluoride/pyridine complex, 6 ml ofpyridine and 12 ml of tetrahydrofuran and stored in a polypropylenecontainer below −10° C.5-O-tert-Butyldimethylsilyl-7-O-trimethylsilylayermectin Bal, used asthe starting material in the following examples, was prepared bytert-butyldimethylsilylating the 5-position of avermectin B1a used as astarting material according to the method of J. Med. Chem., Vol. 25, pp.658-663 (1982) to prepare 5-O-tert-butyldimethylsilyl-avermectin B1a,and then subjecting the product to the method of Reference Example 1.

[0096] 5-O-tert-Butyldimethylsilyl-7-O-trimethylsilylivermectin, used asanother starting material in the following examples, was prepared byusing ivermectin as a starting material according to Reference Examples2 and 3.

[0097] 5-O-tert-Butyldimethylsilyl-7-O-trimethylsilylayermectin B2a as afurther starting material used in the following examples, was preparedby using avermectin B2a as a starting material according to ReferenceExamples 4 and 5.

EXAMPLE 1 Preparation of Compound 1

[0098] 5-O-tert-Butyldimethylsilyl-7-O-trimethylsilylayermectin B1a(2.13 g) obtained in Reference Example 1 was dissolved indichloromethane (1 mL), and a solution of rhodium acetate (11 mg) andethyl diazoacetate in dichloromethane (see below) was added to thesolution. The solution was stirred for one day at room temperature.Diluted aqueous sodium dihydrogenphosphate solution was added to themixture, and the mixture was extracted with dichloromethane. The organiclayer was washed with water and then dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by column chromatography on silica gel with elutingsolvents of hexane/ethyl acetate=4/1 to give 0.98 g of the desiredcompound (yield: 42%).

[0099] HR-FAB-MS: calcd for C₆₁H₁₀₀O₁₆Si₂ [M+Na]⁺ 1167.6488 found1167.6431 IR (KBr) λ_(max)(cm⁻¹):2964, 2933, 1743, 1456, 1384, 1253,1203, 1126, 987, 838

[0100]¹H NMR (270 MHz, CDCl₃, partial data) δ (ppm): 5.78-5.48 (5H, m),5.30 (1H, m), 5.09 (1H, m), 4.94 (1H, m), 4.80 (1H, d, J=3.0 Hz), 4.67(1H, d, J=13.2 Hz), 4.56 (1H, d, J=15.2 Hz), 4.36 (2H, d, J=3.6 Hz),4.25 (2H, q, J=7.5 Hz), 3.97 (1H, br.s), 3.41 (3H, s), 3.35 (3H, s),3.27 (1H, d, J=2.3 Hz), 3.21 (1H, t, J=8.6 Hz), 2.95 (1H, t, J=8.9 Hz),1.77 (3H, s), 1.50 (3H, s), 0.93 (9H, s), 0.14 (15H, s)

[0101]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 170.0, 169.2, 140.0, 136.4,135.3, 134.8, 134.0, 127.8, 124.7, 120.4, 120.3, 118.2, 97.9, 95.4,94.6, 84.4, 83.5, 81.3, 80.5, 78.8, 78.2, 74.3, 69.6, 68.0, 67.7 (*3),67.1, 66.8, 60.5, 60.1, 55.9, 55.7, 46.8, 40.6, 39.4, 35.8, 34.9, 34.4,34.0, 33.9, 30.1, 27.1, 25.5 (*3), 19.8, 19.7, 18.0, 17.6, 16.0, 14.6,13.9, 13.8, 12.6, 11.7, 2.0 (*3), −4.8, −5.1

[0102] <Preparation of Solution of Ethyl Diazoacetate inDichloromethane>

[0103] Glycine ethyl ester hydrochloride (2.8 g) was dissolved intwo-layer solvent of water (5 mL) and dichloromethane (12 mL) and cooledto about −5° C. A cooled solution obtained by dissolving sodium nitrite(1.65 g) in water (5 mL) was added to the solution, and the mixture wasstirred. Cooled 5% aqueous sulfuric acid solution (1.95 g) was furtheradded dropwise to the mixture. The reaction mixture was stirred forabout 10 minutes, while the reaction vessel was cooled so that theinternal temperature did not raise over 1° C. The reaction mixture wastransferred to a separating funnel to separate the aqueous layer, andthen the aqueous layer was extracted with dichloromethane (15 mL). Thecombined organic layer was shaken with a 5% aqueous sodiumhydrogencarbonate solution, and the organic layer was separated. Theorganic layer was dried over anhydrous calcium chloride and filtered,and the resulting solution was used for the reaction as it was.

EXAMPLE 2 Preparation of Compound 2

[0104] Compound 1 (144 mg) was dissolved in tetrahydrofuran (1.5 mL),Solution A (0.4 mL) was added to the solution, and the mixture wasstirred overnight at room temperature. Pyridine was added to thereaction mixture on an ice bath, and an aqueous sodium hydrogencarbonatesolution was added to the reaction mixture for neutralization, and thenthe mixture was extracted with ethyl acetate. The ethyl acetate layerwas dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure to obtain a crude product. Theresulting crude product was purified by column chromatography on silicagel using stepwise elution with eluting solvents ofhexane/2-propanol=15/1, 12/1, 9/1, and 6/1 to give 77 mg of the desiredcompound (yield: 63%).

[0105] HR-FAB-MS: calcd for C₅₂H₇₈O₁₆ [M+Na]⁺ 981.5188 found 981.5234

[0106] IR (KBr) λ_(max)(cm⁻¹): 3465, 2969, 2933, 1754, 1735, 1456, 1380,1199, 1124, 1052, 987 ¹H NMR (270 MHz, CDCl₃, partial data) δ (ppm):5.86-5.70 (4H, m), 5.54 (1H, dd, J=2.6, 9.9 Hz), 5.40 (1H, s), 5.38 (1H,m), 5.31 (1H, d, J=3.3 Hz), 4.96 (1H, m), 4.75 (1H, d, J=3.0 Hz), 4.66(2H, s), 4.20 (2H, q, J=7.3 Hz), 4.19 (2H, d, J=4.0 Hz), 3.95 (1H, d,J=6.3 Hz), 3.91 (1H, br.s), 3.42 (3H, s), 3.35 (3H, s), 3.28 (1H, d,J=2.3 Hz), 3.19 (1H, t, J=8.9 Hz), 2.94 (1H, t, J=8.9 Hz), 1.86 (3H, s),1.27 (3H, t, J=7.3 Hz), 1.22 (3H, d, J=6.3 Hz), 1.19 (3H, d, J=6.3 Hz),1.15 (3H, d, J=6.9 Hz)

[0107]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 173.7, 170.0, 139.5, 138.0,137.9, 136.2, 135.1, 127.7, 124.7, 120.3, 118.2, 118.0, 98.3, 95.7,94.8, 84.8, 81.7, 80.8, 80.3, 79.2, 79.0, 78.6, 74.8, 70.0, 68.4 (*2),68.3, 67.6 (*2), 67.1, 60.6, 56.5, 56.3, 45.6, 40.4, 39.7, 36.6, 35.1,34.8, 34.4, 34.2, 30.5, 27.4, 20.2, 19.9, 18.3, 17.9, 16.3, 15.1, 14.2,12.9, 12.0

EXAMPLE 3 Preparation of Compound 3

[0108] 5-O-tert-Butyldimethylsilyl-7-O-trimethylsilylayermectin B1a (259mg) was dissolved in diethyl ether (2.5 mL). p-Nitrobenzyl bromide (110mg), diisopropylethylamine (100 μl) and silver trifluoromethanesulfonate(137 mg) were added to the solution, and the mixture was stirred at roomtemperature under nitrogen atmosphere for 5 hours. After an aqueoussodium hydrogencarbonate solution was added, the mixture was extractedwith diethyl ether. The diethyl ether layer was dried over anhydrousmagnesium sulfate, and then the solvent was evaporated under reducedpressure to give a crude product. The resulting crude product waspurified by column chromatography on silica gel using stepwise elutionwith eluting solvents of hexane/ethyl acetate=4/1 and 3/1 to give 75 mgof the desired compound (yield: 25%). In addition, 120 mg of thestarting material was recovered.

[0109] HR-FAB-MS: calcd for C₆₄H₉₉NO₁₆Si₂ [M+Na]⁺ 1216.6400 found1216.6403

[0110] IR (KBr) λ_(max) (cm⁻¹): 3436, 2964, 2931, 1743, 1525, 1457,1346, 1124, 1101, 987, 838 ¹H NMR (270 MHz, CDCl₃, partial data) δ(ppm): 8.18 (2H, d, J=8.9 Hz), 7.50 (2H, d, J=8.9 Hz), 5.76-5.47 (6H,m), 5.34 (1H, d, J=3.3 Hz), 5.09 (1H, m), 4.99 (1H, d, J=12.9 Hz), 4.93(1H, m), 4.79 (1H, d, J=3.0 Hz), 4.74 (1H, d, J=12.9 Hz), 4.66 (1H, d,J=14.5 Hz), 4.37 (1H, d, J=13.9 Hz), 4.37 (1H, d, J=5.3 Hz), 3.96 (1H,br.s), 3.41 (3H, s), 3.38 (3H, s), 3.26 (1H, s), 3.23 (1H, t, J=8.9 Hz),3.02 (1H, t, J=8.9 Hz), 1.76 (3H, s), 1.50 (3H, s), 1.16 (3H, d, J=6.9Hz), 0.91 (9H, s), 0.12 (15H, s)

[0111]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 170.4, 147.2, 146.4, 140.4,136.6, 135.8, 135.1, 134.4, 128.0, 127.7 (*2), 125.0, 123.5 (*2), 120.7,120.5, 118.5, 98.2, 95.7, 94.9, 84.7, 83.8, 81.7, 80.6, 79.1, 78.6,74.7, 73.5, 69.5, 68.2, 67.9, 67.5, 67.3, 67.0, 60.3, 56.7, 56.3, 47.1,40.8, 39.7, 36.1, 35.2, 35.1, 34.4, 34.2, 30.4, 27.4, 25.8 (*3), 20.1,20.0, 18.4, 18.0, 16.4, 15.0, 12.9, 12.0, 2.3 (*3), −4.6, −4.8

EXAMPLE 4 Preparation of Compound 4

[0112] Compound 3 (108 mg) was dissolved in tetrahydrofuran (1.5 mL),Solution A (0.4 mL) was added to the solution, and the mixture wasstirred overnight at room temperature. Pyridine was added to the mixtureon ice bath, and an aqueous sodium hydrogencarbonate solution was addedfor neutralization, and then the mixture was extracted with ethylacetate. The ethyl acetate layer was dried over anhydrous magnesiumsulfate, and then the solvent was evaporated under reduced pressure togive a crude product. The resulting crude product was purified by columnchromatography on silica gel using stepwise elution with elutingsolvents of hexane/2-propanol=85/15 and 2/1 to give 80 mg of the desiredcompound (yield: 88%). HR-FAB-MS: calcd for C₅₅H₇₇NO1₆ [M+Na]+1030.5140found 1030.5197

[0113] IR(KBr) λ_(max)(cm⁻¹): 3463, 2967, 2931, 1716, 1606, 1523, 1454,1380, 1346, 1160, 1120, 1103, 1052, 987

[0114]¹H NMR (270 MHz, CDCl₃, partial data) 6 (ppm): 8.19 (2H, d, J=8.9Hz), 7.50 (2H, d, J=8.9 Hz), 5.83-5.70 (4H, m), 5.54 (1H, dd, J=2.6, 9.9Hz), 5.40 (1H, s), 5.38 (2H, m), 5.36 (1H, d, J=3.3 Hz), 5.00 (1H, d,J=12.8 Hz), 4.98 (1H, m), 4.75 (1H, d, J=12.8 Hz), 4.67 (2H, s), 4.27(1H, br.s), 3.43 (3H, s), 3.40 (3H, s), 3.28 (1H, d, J=2.3 Hz), 3.21(1H, t, J=8.9 Hz), 3.02 (1H, t, J=8.9 Hz), 1.86 (3H, s), 1.47 (3H, s)

[0115]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 173.7, 147.2, 146.5, 139.6,137.9, 136.2, 135.1, 127.73 (*2), 127.66, 124.7, 123.5 (*2), 120.3,118.2, 117.9, 98.3, 95.7, 94.8, 84.7, 81.9, 80.6, 80.3, 79.2, 79.0,78.6, 74.8, 73.5, 68.3 (*2), 67.6, 67.3, 64.3 (*2), 56.7, 56.5, 45.6,40.5, 39.7, 36.5, 35.1 (*2), 34.3, 34.2, 30.5, 27.4, 20.2, 19.9, 18.3,18.0, 16.3, 15.1, 12.9, 12.0

EXAMPLE 5 Preparation of Compound 5

[0116] 10% Palladium carbon (4.8 mg) was suspended in ethanol (0.2 mL)and stirred for 30 minutes under hydrogen gas atmosphere. To thissuspension, Compound 4 (34 mg) dissolved in ethanol (0.6 mL) was added,and the mixture was further stirred for 2 hours. The mixture wasfiltered through cerite, and the residue was washed with ethanol. Theethanol solutions were combined, and the solvent was evaporated underreduced pressure to give a crude product. The resulting crude productwas purified by column chromatography on silica gel using stepwiseelution with eluting solvents of dichloromethane/ethyl acetate=2/1,1.5/1, and 1/1 to give 16 mg of the desired compound (yield: 49%).

[0117] HR-FAB-MS: calcd for C₅₅H₇₉NO₁₄ [M+Na]⁺ 1000.5398 found 1000.5435

[0118] IR(KBr) λ_(max)(cm⁻¹): 3448, 2966, 2931, 1724, 1456, 1380, 1340,1288, 1160, 1120, 1054,

[0119]¹H NMR (270 MHz, CDCl₃, partial data) 6 (ppm): 7.15 (2H, d, J=8.4Hz), 6.65 (2H, d, J=8.4 Hz), 5.83-5.70 (4H, m), 5.55 (1H, dd, J=2.3, 9.9Hz), 5.42 (1H, s), 5.40 (1H, m), 5.32 (1H, m), 4.95 (1H, s), 4.75 (1H,d, J=10.2 Hz), 4.74 (1H, m), 4.68 (2H, s), 4.50 (1H, d, J=10.2 Hz), 4.29(1H, br.s), 3.96 (1H, d, J=6.3 Hz), 3.92 (1H, br.s), 3.49 (3H, s), 3.43(3H, s), 3.29 (1H, d, J=2.3 Hz), 3.20 (1H, t, J=8.9 Hz), 3.00 (1H, t,J=8.9 Hz), 1.87 (3H, s), 1.48 (3H, s), 1.14 (3H, d, J=6.9 Hz)

[0120]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 173.7, 146.1, 139.5, 138.1,137.9, 136.3, 135.1, 129.8 (*2), 128.5, 127.7, 124.7, 120.4, 118.2,118.0, 114.9 (*2), 98.4, 95.7, 94.8, 83.7, 81.7, 80.6, 80.3, 79.3, 79.0,78.7, 74.9, 74.8, 68.4, 68.3, 67.71, 67.66, 67.2, 60.4, 57.4, 56.6,45.7, 40.4, 39.7, 36.6, 35.5, 35.1, 34.4, 34.2, 30.5, 27.5, 20.1, 19.9,18.3, 17.9, 16.3, 15.1, 12.9, 12.0

EXAMPLE 6 Preparation of Compound 6

[0121] Compound 1 was dissolved in a water/ethanol (1:1) solution (3mL). Potassium hydroxide (45 mg) was added to the solution, and themixture was stirred overnight at room temperature. A 3% aqueousphosphoric acid solution was added to the mixture, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and then dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by column chromatography on silica gel using stepwise elutionwith eluting solvents of dichloromethane/methanol=20/1, 15/1, and 10/1to give 118 mg of the desired compound (yield: 40%).

[0122] IR(KBr) λ_(max)(cm⁻¹): 3440, 2962, 2933, 1735, 1384, 1197, 1124,1079, 985

[0123]¹H NMR (270 MHz, CDCl₃, partial data) 6 (ppm): 5.73 (3H, m), 5.54(1H, dd, J=2.3, 9.9 Hz), 5.41 (1H, d, J=3.6 Hz), 5.35 (1H, m), 5.31 (1H,s), 4.97 (1H, m), 4.76 (1H, m), 4.68 (1H, d, J=16.2 Hz), 4.57 (1H, d,J=14.2 Hz), 4.42 (1H, d, J=17.2 Hz), 4.08 (1H, d, J=17.2 Hz), 3.92 (1H,br.s), 3.81 (1H, d, J=5.6 Hz), 3.49 (3H, s), 3.43 (3H, s), 3.22 (1H, t,J=9.2 Hz), 2.93 (1H, t, J=9.2 Hz), 1.78 (3H, s), 1.28 (3H, d, J=6.3 Hz),1.23 (3H, d, J=6.3 Hz), 1.15 (3H, d, J=6.9 Hz), 0.92 (9H, s), 0.13 (6H,s)

[0124]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 174.1, 171.7, 140.3, 137.6,137.4, 136.2, 135.1, 127.7, 124.9, 119.3, 118.3, 117.2, 97.9, 95.8,94.9, 86.6, 82.0, 80.6, 80.2, 80.1, 79.3, 74.9, 70.5, 69.5, 68.4, 68.3,67.9, 67.7, 67.0, 56.4, 55.9, 45.8, 40.4, 39.6, 36.6, 35.2, 34.4, 34.3,30.6, 27.5, 25.9 (*3), 20.3, 20.0, 18.40, 18.37, 17.7, 16.4, 15.1, 13.0,12.0, −4.6, −4.9 (it is considered that two peaks overlapped with otherpeaks)

Example 7 Preparation of Compound 7

[0125] Compound 6 (39 mg) was dissolved in tetrahydrofuran (0.6 mL),Solution A (0.3 mL) was added to the solution, and the mixture wasstirred overnight at room temperature. Pyridine was added to the mixtureon an ice bath, and an aqueous sodium hydrogencarbonate solution wasadded for neutralization, and then the mixture was extracted with ethylacetate. The ethyl acetate layer was dried over anhydrous magnesiumsulfate, and then the solvent was evaporated under reduced pressure togive a crude product. The resulting crude product was purified by columnchromatography on silica gel using stepwise elution with elutingsolvents of dichloromethane/methanol=15/1, 10/1, 8/1, and 6/1 to give 11mg of the desired compound (yield: 33%).

[0126] HR-FAB-MS: calcd for C₅₀H₇₃O₁₆ [M+2Na]⁺ 975.4694 found 975.4738

[0127] IR (KBr) λ_(max)(cm⁻¹): 3459, 2967, 2933, 1733, 1454, 1382, 1122,1052, 987

[0128]¹H NMR (270 MHz, CDCl₃, partial data) δ (ppm): 5.76 (4H, m), 5.53(1H, dd, J=1.6, 9.9 Hz), 5.39 (3H, m), 4.97 (1H, m), 4.76 (1H, d, J=3.0Hz), 4.66 (2H, s), 4.40 (1H, d, J=17.2 Hz), 4.28 (1H, d, J=5.6 Hz), 4.10(1H, d, J=17.2 Hz), 3.94 (1H, d, J=6.6 Hz), 3.91 (1H, br.s), 3.47 (3H,s), 3.42 (3H, s), 3.27 (1H, br.s), 3.20 (1H, t, J=9.2 Hz), 2.92 (1H, t,J=9.2 Hz), 2.53 (1H, m), 1.85 (3H, s), 1.48 (3H, s), 1.27 (3H, d, J=6.3Hz), 1.22 (3H, d, J=5.9 Hz), 1.15 (3H, d, J=6.6 Hz)

[0129]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 173.6, 172.1, 139.5, 137.8(*2), 136.2, 135.0, 127.6, 124.7, 120.2, 118.1, 117.9, 97.9, 95.7, 94.8,86.1, 81.8, 80.5, 80.2 (*2), 79.1, 79.0, 74.8, 70.2, 68.3 (*3), 67.5(*2), 66.9, 56.3, 56.9, 51.3, 45.6, 40.3, 39.6, 36.5, 35.0, 34.4 (*2),34.1, 30.4, 27.4, 20.2, 19.8, 18.3, 17.6, 16.3, 15.0, 12.9, 11.9

EXAMPLE 8 Preparation of Compound 8

[0130] Compound 1 (164 mg) was dissolved in dichloromethane (0.7 mL), a1.0 mol/L solution of diisobutylaluminium hydride in toluene (0.5 mL)was added dropwise to the solution at −60° C., and the mixture wasstirred at the same temperature for 30 minutes. After the mixture wasdiluted with dichloromethane, methanol was added to the mixture toinactivate excessive reagents, and cerite and sodium sulfate decahydratewere added to the mixture. The mixture was stirred for 30 minutes atroom temperature. The mixture was filtered, and the residue was washedwith ethyl acetate. The organic layers were combined and concentratedunder reduced pressure to give a crude product. The resulting crudeproduct was purified by column chromatography on silica gel usingstepwise elution with eluting solvents of dichloromethane/methanol=60/1,50/1, and 40/1 to give 49 mg of the desired compound (yield: 30%).

[0131] IR (KBr) λ_(max)(cm⁻¹): 3459, 2967, 2933, 1733, 1454, 1382, 1122,1052, 987

[0132]¹H NMR (270 MHz, CDCl₃, partial data) δ (ppm): 9.66 (1H, s), 5.69(4H, m), 5.51 (1H, dd, J=2.3, 9.9 Hz), 5.47 (1H, br.s), 5.34 (1H, m),5.09 (1H, m), 4.93 (1H, m), 4.78 (1H, br.s), 4.65 (1H, d, J=14.8 Hz),4.55 (1H, d, J=14.8 Hz), 4.36 (1H, br.s), 4.32 (1H, d, J=5.9 Hz), 3.39(3H, s), 3.32 (3H, s), 3.26 (1H, d, J=2.3 Hz), 3.19 (1H, t, J=8.9 Hz),2.90 (1H, t, J=8.9 Hz), 2.59 (1H, m), 1.75 (3H, s), 1.49 (3H, s), 1.25(6H, m), 1.17 (3H, d, J=6.6 Hz), 0.91 (9H, s), 0.12 (15H, s)

[0133]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm) 201.2, 170.6, 140.6, 136.7,136.0, 135.3, 134.5, 128.1, 125.2, 120.8, 120.6, 118.6, 98.2, 95.9,95.0, 85.7, 83.9, 81.8, 80.7, 79.2, 78.5, 76.4, 74.9, 69.6, 68.4, 68.1,67.6, 67.2, 67.1, 56.4, 56.2, 47.3, 41.0, 39.9, 36.2, 35.3, 34.8, 34.5,34.4, 30.6, 27.5, 25.9 (*3), 20.3, 20.2, 18.5 (*2), 18.0, 16.5, 15.1,13.0, 12.2, 2.6 (*3), −4.3, −4.5

EXAMPLE 9 Preparation of Compound 9

[0134] Compound 8 (22.7 mg) was dissolved in a mixture of pyridine (0.1mL) and ethanol (0.1 mL), hydroxylamine hydrochloride (4.3 mg) was addedto the solution, and the mixture was stirred overnight at roomtemperature. A saturated aqueous sodium hydrogencarbonate solution wasadded to the mixture, the mixture was extracted with ethyl acetate, andthe organic layer was dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the resulting crudeproduct was dissolved in tetrahydrofuran (0.8 mL). Solution A (0.3 mL)was added to the solution, and the mixture was stirred overnight at roomtemperature. Pyridine was added to the mixture on an ice bath, and anaqueous sodium hydrogencarbonate solution was added for neutralization,and then the mixture was extracted with ethyl acetate. The ethyl acetatelayer was dried over anhydrous magnesium sulfate, and then the solventwas evaporated under reduced pressure to give a crude product. Theresulting crude product was purified on a thin layer silica gel platewith eluting solvents of hexane/2-propanol=85/15 anddichloromethane/methanol=4/1 to give 5.8 mg of the desired compound(yield: 30%).

[0135] HR-FAB-MS: calcd for C₅₀H₇₅NO15[M+Na]+952.5034 found 952.5037

[0136] IR (KBr) X max(cm⁻¹): 3428, 2967, 2931, 1735, 1716, 1454, 1382,1120, 1052, 985

EXAMPLE 10 Preparation of Compound 10

[0137] Compound 6 (121 mg) was dissolved in dichloromethane (0.5 ml),morpholine (19 μl), N-hydroxybenzotriazole (17 mg) and WSCIhydrochloride (23 mg) were added to the solution, and the mixture wasstirred at room temperature for two days. A 1% aqueous phosphoric acidsolution was added to the mixture, and the mixture was extracted withethyl acetate. The organic layer was washed with water and a saturatedaqueous sodium hydrogencarbonate solution and then dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by column chromatography on silica gelusing stepwise elution with eluting solvents of hexane/2-propanol=85/15,4/1, and 3/1 to give a crude product.

[0138] The resulting crude product was dissolved in tetrahydrofuran (1.5mL), Solution A (0.5 mL) was added to the solution, and the mixture wasstirred overnight at room temperature. Pyridine was added to the mixtureon an ice bath, and an aqueous sodium hydrogencarbonate solution wasadded for neutralization, and then the mixture was extracted with ethylacetate. The ethyl acetate layer was dried over anhydrous magnesiumsulfate, and then the solvent was evaporated under reduced pressure togive a crude product. The resulting crude product was purified by columnchromatography on silica gel using stepwise elution with elutingsolvents of dichloromethane/methanol=25/1 and 20/1 to give 74 mg of thedesired compound (yield: 68%).

[0139] HR-FAB-MS: calcd for C₅₄H₈₁NO₁₆ [M+Na]+1022.5453 found 1022.5460

[0140] IR(KBr) λ_(max)(cm⁻¹): 3473, 2967, 2931, 1733, 1654, 1456, 1382,1272, 1118, 1052, 987 ¹H NMR (270 MHz, CDCl₃, partial data) δ (ppm):5.77 (3H, m), 5.54 (1H, dd, J=2.3, 9.9 Hz), 5.37 (3H, m), 4.95 (1H, m),4.75 (1H, d, J=3.0 Hz), 4.67 (1H, s), 4.51 (1H, d, J=12.8 Hz), 4.28 (1H,d, J=12.8 Hz), 4.26 (1H, s), 3.95 (1H, d, J=6.3 Hz), 3.42 (3H, s), 3.35(3H, s), 3.28 (1H, d, J=2.0 Hz), 3.19 (1H, t, J=8.9 Hz), 2.92 (1H, t,J=8.9 Hz), 1.85 (3H, s), 1.27 (3H, d, J=6.3 Hz), 1.22 (3H, d, J=6.3 Hz),1.15 (3H, d, J=6.9 Hz) ¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 173.7, 167.7,139.6, 138.0, 137.9, 136.3, 135.1, 127.7, 124.7, 120.3, 118.2, 118.0,98.2, 95.7, 94.8, 84.6, 81.8, 81.6, 80.6, 80.3, 79.2, 79.0, 78.2, 74.8,71.8, 68.4, 68.3, 67.6, 67.2, 67.1, 66.8, 66.7, 56.5, 56.0, 45.6, 45.5,42.0, 40.4, 39.7, 36.6, 35.1, 34.7, 34.4, 34.2, 30.5, 27.4, 20.2, 19.9,18.3, 17.9, 16.3, 15.1, 12.9, 12.0

EXAMPLE 11 Preparation of Compound 11

[0141] Compound 6 (121 mg) was dissolved in dichloromethane (0.5 mL).Piperidine (19 μl), N-hydroxybenzotriazole (17 mg) and WSCIhydrochloride (23 mg) were added to the solution, and the mixture wasstirred at room temperature for two days. A 1% aqueous phosphoric acidsolution was added to the mixture, the mixture was extracted with ethylacetate, and the organic layer was washed with water and a saturatedaqueous sodium hydrogencarbonate solution and then dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by column chromatography on silica gel witheluting solvents of hexane/2-propanol=85/15 to give a crude product.

[0142] The resulting crude product was dissolved in tetrahydrofuran (1.5mL), Solution A (0.5 mL) was added to the solution, and the mixture wasstirred overnight at room temperature. Pyridine was added to the mixtureon an ice bath, and an aqueous sodium hydrogencarbonate solution wasadded for neutralization, and then the mixture was extracted with ethylacetate. The ethyl acetate layer was dried over anhydrous magnesiumsulfate, and then the solvent was evaporated under reduced pressure togive a crude product. The resulting crude product was purified by columnchromatography on silica gel using stepwise elution with elutingsolvents of dichloromethane/methanol=25/1 and 20/1 to give 87 mg of thedesired compound (yield: 81%).

[0143] HR-FAB-MS: calcd for C₅₅H₈₃NO₁₅ [M+Na]⁺ 1020.5660 found 1020.5688

[0144] IR (KBr) λ_(max)(cm⁻¹): 3471, 2967, 2933, 1737, 1718, 1645, 1452,1382, 1160, 1120, 1052, 987

[0145]¹H NMR (270 MHz, CDCl₃, partial data) δ (ppm): 5.82-5.70 (4H, m),5.53 (1H, dd, J=2.3, 9.9 Hz), 5.37 (3H, m),4.91 (1H, m), 4.74 (1H, d,J=3.0 Hz), 4.66 (1H, s), 4.51 (1H, d, J=12.5 Hz), 4.26 (1H, s), 4.24(1H, d, J=12.5 Hz), 4.03 (1H, br.s), 3.41 (3H, s), 3.36 (3H, s), 3.27(1H, d, J=2.0 Hz), 3.19 (1H, t, J=8.9 Hz), 2.91 (1H, t, J=8.9 Hz), 1.84(3H, s), 1.15 (3H, d, J=6.9 Hz)

[0146]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 173.6, 167.3, 139.5, 138.0,137.9, 136.2, 135.1, 127.7, 124.7, 120.3, 118.2, 118.0, 98.2, 95.7,94.8, 84.5, 81.8, 80.7, 80.3, 79.2, 79.1, 78.4, 77.2, 74.9, 71.8, 68.3(*2), 67.6, 67.3, 67.2, 56.5, 56.2, 46.0, 45.6, 42.7, 40.4, 39.7, 36.5,35.1, 34.8, 34.4, 34.2, 30.5, 27.4, 26.4, 25.4, 24.4, 20.1, 19.9, 18.3,17.9, 16.3, 15.0, 12.9, 12.0

EXAMPLE 12 Preparation of Compound 12

[0147] Compound 8 (27.0 mg) was dissolved in a mixture of pyridine (0.1mL) and ethanol (0.2 mL), methoxyamine hydrochloride (7.8 mg) was addedto the solution, and the mixture was stirred at room temperature for 90minutes. A saturated aqueous sodium hydrogencarbonate solution was addedto the mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the resulting crude productwas dissolved in tetrahydrofuran (0.8 mL). Solution A (0.4 mL) was addedto the solution, and the mixture was stirred overnight at roomtemperature. Then, the reaction mixture was treated and purified in themanners similar to those in Example 9 to give 3.9 mg of the desiredcompound (yield: 17%).

[0148] HR-FAB-MS: calcd for C₅₁H₇₇NO₁₅ [M+Na]⁺ 966.5191 found 966.5220

[0149] IR (KBr) λ_(max)(cm⁻¹): 3457, 2966, 2933, 1733, 1456, 1380, 1160,1120, 1047, 987

EXAMPLE 13 Preparation of Compound 13

[0150] Compound 6 (169 mg) was dissolved in dichloromethane (0.3 mL),furfuryl alcohol (50 μl), 4-dimethylaminopyridine (10 mg) and WSCIhydrochloride (63 mg) were added to the solution, and the mixture wasstirred overnight at room temperature. A 5% sodium aqueousdihydrogenphosphate solution was added to the mixture, and the mixturewas extracted with dichloromethane. The organic layer was washed withwater and a saturated aqueous sodium hydrogencarbonate solution and thendried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by column chromatographyon silica gel using stepwise elution with eluting solvents ofhexane/ethyl acetate=4/1, 2/1, and 1/1 to give a crude product. Theresulting crude product was dissolved in tetrahydrofuran (2 mL),Solution A (0.3 mL) was added to the solution, and the mixture wasstirred overnight at room temperature. Pyridine was added to the mixtureon an ice bath, and an aqueous sodium hydrogencarbonate solution wasadded for neutralization, and then the mixture was extracted with ethylacetate. The ethyl acetate layer was dried over anhydrous magnesiumsulfate, and then the solvent was evaporated under reduced pressure togive a crude product. The resulting crude product was purified by columnchromatography on silica gel using stepwise elution with elutingsolvents of hexane/2-propanol=12/1, 9/1, 6/1, and 3/1 to give 49 mg ofthe desired compound (yield: 33%).

[0151] HR-FAB-MS: calcd for C₅₅H₇₈O₁₇ [M+Na]⁺ 1033.5137 found 1033.5155

[0152] IR (KBr) λ_(max)(cm⁻¹): 3467, 2967, 2933, 1735, 1452, 1382, 1294,1165, 1191, 1122, 987

[0153]¹H NMR (270 MHz, CDCl₃, partial data) δ (ppm): 7.40 (1H, d, J=2.0Hz), 6.44 (1H, dd, J=2.0, 3.3 Hz), 6.41 (1H, d, J=3.3 Hz), 5.85-5.69(5H, m), 5.54 (1H, dd, J=2.3, 9.9 Hz), 5.41 (1H, s), 5.38 (1H, m), 5.32(1H, s), 5.12 (2H, d, J=2.3 Hz), 4.96 (1H, m), 4.85 (1H, s), 4.67 (1H,s), 4.39 (2H, s), 3.42 (3H, s), 3.31 (3H, s), 3.28 (1H, d, J=2.3 Hz),3.19 (1H, t, J=9.2 Hz), 2.94 (1H, t, J=9.2 Hz), 1.86 (3H, s), 1.27 (3H,d, J=6.3 Hz), 1.22 (3H, d, J=6.3 Hz), 1.15 (3H; d; J=6.9 Hz).

[0154]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 173.7, 170.2, 149.1, 143.3,139.5, 138.1, 137.9, 136.2, 135.1, 127.7, 124.7, 120.4, 118.2, 118.0,111.0, 110.6, 98.3, 95.7, 94.8, 84.8, 81.7, 80.8, 80.3, 79.3, 79.0,78.5, 74.9, 69.8, 68.4, 68.3 (*2), 67.7, 67.2, 67.1, 58.0, 56.6, 56.1,45.7, 40.4, 39.7, 36.6, 35.1, 34.8, 34.4, 34.2, 30.5, 27.5, 20.2, 19.9,18.3, 17.9, 16.3, 15.1, 12.9, 12.0

EXAMPLE 14 Preparation of Compound 14

[0155] Compound 1 (1.10 g) was dissolved in tetrahydrofuran (2.0 mL).Under nitrogen atmosphere, a 1.0 mol/L solution of super hydride(lithium triethylbrohydride) in tetrahydrofuran (5.0 mL) was slowlyadded dropwise to the solution, and the mixture was stirred. After 15minutes, water was added to the mixture to inactivate excessivereagents, and then a 30% aqueous hydrogen peroxide solution (4.0 mL) wasadded to the mixture, and the mixture was distributed between a 2%aqueous phosphoric acid solution and diethyl ether. The collectedorganic layer was washed with water and an aqueous sodiumhydrogencarbonate solution and then dried over anhydrous sodium sulfate,and the solvent was evaporated under reduced pressure to give a crudeproduct. The resulting crude product was purified by columnchromatography on silica gel using stepwise elution with elutingsolvents of hexane/ethyl acetate=3/1 and 1.5/1 to give 698 mg of thedesired compound (yield: 66%).

[0156] HR-FAB-MS: calcd for C₅₉H₉₈O₁₅Si₂ [M+Na]⁺ 1125.6342 found1125.6417 IR (KBr) λ_(max)(cm⁻¹): 3455, 2962, 2933, 1743, 1457, 1382,1253, 1203, 1124, 987, 838

[0157]¹H NMR (270 MHz, CDCl₃, partial data) δ (ppm): 5.76-5.46 (6H, m),5.33 (1H, d, J=3.3 Hz), 5.08 (1H, m), 4.93 (1H, m), 4.77 (1H, m), 4.65(1H, d, J=14.8 Hz), 4.54 (1H, d, J=14.5 Hz), 4.35 (1H, m), 3.95 (1H,br.s), 3.41 (3H, s), 3.39 (3H, s), 3.25 (1H, s), 3.21 (1H, t, J=8.6 Hz),2.97 (1H, t, J=8.9 Hz), 1.75 (3H, s), 1.48 (3H, s), 1.15 (3H, d, J=6.9Hz), 0.91 (9H, s), 0.11 (15H, s)

[0158]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 170.4, 140.4, 136.6, 135.8,135.1, 134.4, 128.0, 125.0, 120.7, 120.5, 118.5, 98.0, 95.7, 94.9, 85.1,83.8, 81.7, 80.6, 80.3, 79.1, 78.0, 74.72, 74.67, 69.5, 68.2, 68.0,67.9, 67.4, 67.0, 62.7, 56.3, 56.2, 47.1, 40.8, 39.7, 36.1, 35.2, 34.8,34.3, 34.2, 30.4, 27.4, 25.8 (*3), 20.1, 20.0, 18.3, 17.7, 16.3, 15.0,12.9, 12.0, 2.3 (*3), −4.6, −4.8

EXAMPLE 15 Preparation of Compound 15

[0159] Compound 14 (107 mg) was dissolved in tetrahydrofuran (0.8 mL),Solution A (0.4 mL) was added to the solution, and the mixture wasstirred overnight at room temperature. Pyridine was added to the mixtureon an ice bath, and an aqueous sodium hydrogencarbonate solution wasadded for neutralization, and then the mixture was extracted with ethylacetate. The ethyl acetate layer was dried over anhydrous magnesiumsulfate, and then the solvent was evaporated under reduced pressure togive a crude product. The resulting crude product was purified by columnchromatography on silica gel using stepwise elution with elutingsolvents of dichloromethane/methanol=40/1 and 20/1 to give 79 mg of thedesired compound (yield: 88%).

[0160] HR-FAB-MS: calcd for C₅₀H₇₆O₁₅ [M+Na]⁺ 939.5082 found 939.5066

[0161] IR (KBr) λ_(max)(cm⁻¹): 3455, 2967, 2933, 1735, 1456, 1382, 1160,1122, 1052, 985

[0162]¹H NMR (270 MHz, CDCl₃, partial data) δ (ppm): 5.88-5.71 (4H, m),5.53 (1H, dd, J=2.6, 9.9 Hz), 5.42 (1H, s), 5.40 (1H, m), 5.37 (1H, m),4.99 (1H, m), 4.77 (1H, d, J=3.0 Hz), 4.68 (2H, s), 4.29 (1H, br.d,J=4.6 Hz), 4.03 (1H, br.s), 3.97 (1H, d, J=6.3 Hz), 3.45 (3H, s), 3.43(3H, s), 3.30 (1H, d, J=2.0 Hz), 3.23 (1H, t, J=8.9 Hz), 3.00 (1H, t,J=8.9 Hz), 1.87 (3H, s), 1.49 (3H, s), 1.16 (3H, d, J=6.9 Hz)

[0163]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 173.7, 139.6, 138.0 (*2),136.3, 135.1, 127.7, 124.7, 120.4, 118.3, 118.0, 98.2, 95.8, 94.9, 85.2,81.9, 80.4 (*2), 79.3, 79.1, 78.0, 74.9, 74.7, 68.4, 68.3, 68.1, 67.7,67.2, 62.8, 60.4, 56.5, 56.4, 45.7, 40.5, 39.8, 36.6, 35.2, 34.8, 34.4,34.2, 30.6, 27.5, 20.2, 19.9, 18.4, 17.8, 16.4, 15.1, 12.9, 12.0

EXAMPLE 16 Preparation of Compound 16

[0164] Compound 14 (0.44 g) was dissolved in pyridine (0.80 mL), tosylchloride (0.38 g) and 4-dimethylaminopyridine (3.7 mg) were added to thesolution, and the mixture was stirred at a room temperature for 2 hours.A saturated aqueous sodium hydrogencarbonate solution was added to themixture, and the mixture was extracted with ethyl acetate. The collectedethyl acetate layer was successively washed with purified water andsaturated brine and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure to give a crude product. The resultingcrude product was purified by column chromatography on silica gel usingg of Compound 16 (yield: 65%).

[0165] HR-FAB-MS: calcd for C₆₆H₁₀₄O₁₇SSi₂ [M+Na]⁺ 1279.6431 found1279.6379

EXAMPLE 17 Preparation of Compound 17

[0166] Compound 16 (68 mg) was dissolved in tetrahydrofuran (1.2 mL),Solution A (400 μl) was added to the solution, and the mixture wasstirred overnight at room temperature. Then, the reaction mixture wastreated and purified in the manners similar to those in Example 2 togive 62 mg of the desired compound (yield: 83%). HR-FAB-MS: calcd forC₅₇H82017S [M+Na]⁺ 1093.5170 found 1093.5127

EXAMPLE 18 Preparation of Compound 18

[0167] Compound 14 (0.30 g) was dissolved in dichloromethane (2.7 mL),triethylamine (0.38 mL), triphenylphosphine (0.18 g) and carbontetrabromide (0.22 g) were added to the solution, and the mixture wasstirred at room temperature for 30 minutes. A saturated aqueous sodiumhydrogencarbonate solution was added to the mixture, and then themixture was extracted with dichloromethane. The collecteddichloromethane layer was washed with saturated brine and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure to give a crude product. The resulting crude product waspurified by column chromatography on silica gel with eluting solvents ofhexane/ethyl acetate=5/1 to give 0.29 g of the desired substance (yield:91%).

[0168] IR(KBr) λ_(max)(cm⁻¹): 3423, 2964, 2933, 1743, 1458, 1383, 1340,1306, 1254, 1203, 1161, 1124, 1101, 1054, 987

[0169]¹H NMR (270 MHz, CDCl₃, partial data) δ (ppm): 5.66 (4H, m), 5.50(1H, dd, J=2.3, 9.9 Hz), 5.47 (1H, br.d, J=2.3 Hz), 5.30 (1H, d, J=3.0Hz), 5.10 (1H, m), 4.93 (1H, m), 4.86 (1H, d, J=3.3 Hz), 4.66 (1H, d,J=14.2 Hz), 4.55 (1H, d, J=14.1 Hz), 4.37 (1H, m), 3.96 (1H, br.s), 3.81(1H, d, J=5.3 Hz), 3.46 (2H, t, J=6.2 Hz), 3.41 (6H, s), 3.26 (1H, d,J=2.0 Hz), 3.21 (1H, t, J=8.9 Hz), 2.86 (1H, t, J=9.1 Hz), 2.57 (1H, m),1.76 (3H, s), 1.50 (3H, s), 1.28 (3H, d, J=6.6 Hz), 1.23 (3H, d, J=6.9Hz), 1.16 (3H, d, J=6.9 Hz), 0.92 (9H, s), 0.13 (15H, s)

[0170]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 170.5, 140.4, 136.7, 135.8,135.2, 134.4, 128.0, 125.0, 120.7, 120.5, 118.5, 98.3, 95.8, 94.9, 84.8,83.8, 81.7, 80.7, 80.6, 79.1, 78.3, 74.7, 72.6, 69.5, 68.3, 68.0, 67.5(*2), 67.0, 57.0, 56.4, 47.2, 40.9, 39.7, 36.1, 35.2 (*2), 34.4, 34.2,31.0, 30.4, 27.4, 25.8 (*3), 20.2, 20.1, 18.4 (*2), 17.9, 16.4, 15.0,12.9, 12.1, 2.4 (*3), −4.5, −4.8

EXAMPLE 19 Preparation of Compound 19

[0171] Compound 18 (0.30 g) was dissolved in dimethyl sulfoxide (2.6mL), sodium azide (33 mg) was added to the solution, and the mixture wasstirred at 40° C. for 4.5 hours. Purified water was added to themixture, and then the mixture was extracted with ethyl acetate. Thecollected ethyl acetate layer was washed with water and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure to give a crude product. The resulting crude product waspurified by column chromatography on silica gel with eluting solvents ofhexane/ethyl acetate=5/1 to give 0.28 g of the desired substance (yield:95%).

[0172] HR-FAB-MS: calcd for C₅₉H₉₇O₁₄N₃Si₂Na [M+Na]⁺ 1150.6407 found1150.6395

[0173] IR(KBr) λ_(max)(cm⁻¹): 3429, 2962, 2933, 2104, 1743, 1460, 1385,1338, 1309, 1252, 1205, 1161, 1124, 1083, 1055, 987

[0174]¹H NMR (270 MHz, CDCl₃, partial data) δ (ppm): 5.65 (4H, m), 5.49(1H, dd, J=2.0, 9.9 Hz), 5.46 (1H, br.s), 5.30 (1H, d, J=3.0 Hz), 5.09(1H, m), 4.92 (1H, m), 4.77 (1H, d, J=2.6 Hz), 4.64 (1H, d, J=14.7 Hz),4.53 (1H, d, J=14.7 Hz), 4.36 (1H, m), 3.95 (1H, br.s), 3.80 (1H, d,J=5.3 Hz), 3.40 (3H, s), 3.39 (3H, s), 3.25 (1H, d, J=2.3 Hz), 3.20 (1H,t, J=8.9 Hz), 2.83 (1H, t, J=8.9 Hz), 2.55 (1H, m), 1.75 (3H, s), 1.48(3H, s), 1.25 (3H, d, J=6.9 Hz), 1.22 (3H, d, J=6.9 Hz), 1.15 (3H, d,J=6.9 Hz), 0.91 (9H, s), 0.11 (15H, s)

[0175]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 170.4, 140.3, 136.6, 135.8,135.1, 134.3, 127.9, 124.9, 120.7, 120.5, 118.5, 98.2, 95.7, 94.9, 84.8,83.7, 81.7, 80.6, 80.5, 79.1, 78.2, 74.7, 71.4, 69.4, 68.2, 67.9, 67.4(*2), 67.0, 56.7, 56.3, 51.2, 47.1, 40.8, 39.7, 36.1, 35.2, 35.0, 34.3,34.2, 30.4, 27.4, 25.8 (*3), 20.1, 20.0, 18.3 (*2), 17.7, 16.3, 15.0,12.9, 12.0, 2.3 (*3), −4.6, −4.8

EXAMPLE 20 Preparation of Compound 20

[0176] Compound 19 (50 mg) was dissolved in tetrahydrofuran (500 μl),Solution A (50 μl) was added to the solution, and the mixture wasstirred overnight at room temperature. Then, the reaction mixture wastreated and purified in the manners similar in those in Example 9 togive 36 mg of the desired compound (yield: 87%).

[0177] HR-FAB-MS: calcd for C₅₀H₇₅O₁₄N₃ [M+Na]⁺ 964.5147 found 964.5145

[0178] IR(KBr) λ_(max)(cm⁻¹): 3675, 2968, 2933, 2162, 1718, 1452, 1383,1344, 1294, 1196, 1163, 1120, 1051, 987

[0179]¹H NMR (270 MHz, CDCl₃, partial data) δ (ppm): 5.86 (1H, m), 5.74(3H, m), 5.54 (1H, dd, J=2.6, 9.9 Hz), 5.41 (1H, br.s), 5.40 (1H, m),5.34 (1H, d, J=3.0 Hz), 4.97 (1H, m), 4.73 (1H, d, J=3.0 Hz), 4.67 (2H,s), 4.28 (1H, m), 3.96 (1H, d, J=6.6 Hz), 3.93 (1H, br.s), 3.43 (6H, s),3.29 (1H, d, J=2.0 Hz), 3.21 (1H, t, J=9.1 Hz), 2.85 (1H, t, J=9.1 Hz),2.53 (1H, m), 1.87 (3H, s), 1.48 (3H, s), 1.27 (3H, d, J=6.3 Hz), 1.23(3H, d, J=5.9 Hz), 1.16 (3H, d, J=6.9 Hz)

[0180]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 173.7, 139.6, 138.0 (*2),136.3, 135.1, 127.7, 124.9, 120.4, 118.2, 118.0, 98.3, 95.7, 94.9, 84.9,81.8, 80.6, 80.3, 79.3, 79.0, 78.3, 74.9, 71.4, 68.4, 68.3, 67.9, 67.7,67.5, 67.2, 56.8, 56.6, 51.3, 45.7, 40.4, 39.7, 36.6, 35.1 (*2), 34.5,34.2, 30.5, 27.5, 20.2, 19.9, 18.3, 17.8, 16.3, 15.1, 12.9, 12.0

EXAMPLE 21 Preparation of Compound 21

[0181] Compound 19 (0.25 g) was dissolved in tetrahydrofuran (2.2 mL),triphenylphosphine (0.12 g) was added to the solution, and the mixturewas stirred at 40° C. for 2.5 hours. Purified water and 30% aqueousammonia (2 drops) were added to the mixture, and the mixture wasextracted with ethyl acetate. The collected ethyl acetate layer waswashed with water and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure to give a crude product. Theresulting crude product was purified by column chromatography on silicagel with eluting solvents of chloroform/methanol=50/1 to give 0.24 g ofthe desired substance (yield: 100%). As chloroform for the elutingsolvent, ten drops of 30% aqueous ammonia was added dropwise to 100 mLof chloroform and used.

[0182] HR-FAB-MS: calcd for C₅₉H₉₉O₁₄NSi₂ [M+Na]⁺ 1124.6502 found1124.6499

[0183] IR(KBr) λ_(max)(cm⁻¹): 3467, 2964, 2933, 1743, 1458, 1383, 1338,1306, 1254, 1203, 1161, 1124, 1057, 987

[0184]¹H NMR (270 MHz, CDCl₃, partial data) δ (ppm): 5.70 (4H, m), 5.51(1H, dd, J=2.3, 9.9 Hz), 5.48 (1H, br.d, J=2.0 Hz), 5.31 (1H, d, J=3.0Hz), 5.10 (1H, m), 4.94 (1H, m), 4.79 (1H, d, J=2.6 Hz), 4.66 (1H, d,J=14.1 Hz), 4.56 (1H, d, J=14.1 Hz), 4.37 (1H, m), 3.96 (1H, br.s), 3.82(1H, d, J=5.3 Hz), 3.41 (6H, s), 3.24 (2H, m), 2.87 (1H, t, J=9.1 Hz),2.57 (1H, m), 1.77 (3H, s), 1.50 (3H, s), 1.25 (3H, d, J=6.3 Hz), 1.24(3H, d, J=5.6 Hz), 1.17 (3H, d, J=6.9 Hz), 0.92 (9H, s), 0.13 (15H, s)

[0185]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 170.5, 140.4, 136.7, 135.9,135.2, 134.4, 128.0, 125.0, 120.7, 120.5, 118.5, 98.2, 95.8, 95.0, 84.8,83.8, 81.7, 80.7, 80.5, 79.2, 78.1, 74.8, 69.5 (*2), 68.3, 68.0, 67.8,67.5, 67.0, 56.7, 56.4, 47.2, 42.0, 40.0, 39.8, 36.1, 35.2, 35.0, 34.4,34.3, 30.5, 27.4, 25.8 (*3), 20.2, 20.1, 18.4 (*2), 17.9, 16.4, 15.0,12.9, 12.1, 2.4 (*3), −4.5, −4.7

EXAMPLE 22 Preparation of Compound 22

[0186] Compound 21 (70 mg) was dissolved in tetrahydrofuran (1.0 mL),Solution A (70 μl) was added to the solution, and the mixture wasstirred overnight at room temperature. Then, the mixture was treated inthe manner similar to that in Example 2. The resulting product waspurified by column chromatography on silica gel with eluting solvents ofchloroform/methanol=20/1 to give 54 mg of the desired compound (yield:92%). As chloroform for the eluting solvent, ten drops of 30% aqueousammonia was added dropwise to 100 mL of chloroform and used. HR-FAB-MS:calcd for C₅₀H77014N [M+Na]⁺ 938.5242 found 938.5243

[0187] IR(KBr) λ_(max)(cm⁻¹): 3481, 2966, 2931, 2162, 1722, 1456, 1383,1342, 1294, 1194, 1163, 1120, 1055, 987

[0188]¹H NMR (270 MHz, CDCl₃, partial data) δ (ppm): 5.84 (1H, m), 5.75(3H, m), 5.53 (1H, dd, J=2.5, 9.7 Hz), 5.40 (1H, br.s), 5.36 (1H, m),5.32 (1H, d, J=3.0 Hz), 4.96 (1H, m), 4.75 (1H, d, J=3.3 Hz), 4.66 (2H,s), 4.27 (1H, br.d, J=5.9 Hz), 3.94 (1H, d, J=6.3 Hz), 3.91 (1H, s),3.42 (6H, s), 3.27 (1H, d, J=2.0 Hz), 3.20 (1H, t, J=8.9 Hz), 2.85 (1H,t, J=8.9 Hz), 2.30 (1H, m), 1.85 (3H, s), 1.47 (3H, s), 1.24 (3H, d,J=5.6 Hz), 1.22 (3H, d, J=5.6 Hz), 1.14 (3H, d, J=5.6 Hz)

[0189]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 173.6, 139.6, 137.9, 137.8,136.2, 135.1, 127.7, 124.7, 120.3, 118.2, 118.0, 98.2, 95.7, 94.8, 84.7,81.8, 80.5, 80.3, 79.3, 79.2, 78.1, 74.8, 68.3 (*3), 67.7, 67.6 (*2),67.2, 56.8, 56.5, 45.7, 42.2, 40.4, 39.7, 36.6, 35.1 (*2), 34.4, 34.2,30.5, 27.4, 20.1, 19.9, 18.3, 17.9, 16.3, 15.0, 12.9, 12.0

EXAMPLE 23 Preparation of Compound 23

[0190] Compound 18 (0.42 g) was dissolved in tetrahydrofuran (0.50 mL),Solution A (50 μl) was added to the solution, and the mixture wasstirred overnight at room temperature. Then, the reaction mixture wastreated and purified in the manners similar to those in Example 2 togive 0.31 g of the desired compound (yield: 89%).

[0191] HR-FAB-MS: calcd for C₅₀H₇₅O₁₄Br [M+Na]⁺ 1001.4238 found1001.4243

[0192] IR(KBr) λ_(max)(cm⁻¹): 3446, 2968, 2933, 1712, 1454, 1381, 1340,1274, 1194, 1161, 1120, 1053, 985

[0193]¹H NMR (270 MHz, CDCl₃, partial data) δ (ppm): 5.83 (1H, m), 5.73(3H, m), 5.53 (1H, dd, J=2.3, 9.7 Hz), 5.40 (1H, br.s), 5.36 (1H, m),5.31 (1H, d, J=3.3 Hz), 4.97 (1H, m), 4.75 (1H, d, J=3.3 Hz), 4.67 (2H,s), 4.22 (1H, m), 4.12 (1H, m), 4.02 (1H, br.s), 3.95 (1H, d, J=6.3 Hz),3.91 (1H, br.s), 3.45 (2H, d, J=6.3 Hz), 3.42 (6H, s), 3.28 (1H, d,J=2.3 Hz), 3.19 (1H, t, J=8.9 Hz), 2.86 (1H, t, J=8.9 Hz), 2.51 (1H, m),2.00 (1H, m), 1.85 (3H, s), 1.76 (1H, m), 1.47 (3H, s), 1.27 (3H, d,J=6.3 Hz), 1.22 (3H, d, J=6.3 Hz), 1.14 (3H, d, J=6.9 Hz)

[0194]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 173.7, 139.6, 138.0, 137.9,136.2, 135.1, 127.7, 124.7, 120.3, 118.2, 118.0, 98.4, 95.7, 94.8, 84.3,81.8, 80.8, 80.3, 79.2, 79.0, 78.3, 74.8, 72.6, 68.4, 68.3 (*2), 67.6,67.5, 67.1, 57.0, 56.6, 45.6, 40.4, 39.7, 36.6, 35.2, 35.1, 34.4, 34.2,31.1, 30.5, 27.5, 20.2, 19.9, 18.3, 17.9, 16.3, 15.1, 12.9, 12.0

EXAMPLE 24 Preparation of Compound 24

[0195] Compound 14 (0.10 g) was dissolved in dichloromethane (1.0 mL),imidazole (30 mg), triphenylphosphine (60 mg) and iodine (30 mg) wereadded to the solution, and the mixture was stirred at room temperaturefor 4 hours. Excess iodine was reduced with a saturated aqueous sodiumsulfite solution, and then the mixture was extracted withdichloromethane. The collected dichloromethane layer was washed withsaturated brine and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure to give a crude product. The resultingcrude product was purified by column chromatography on silica gel witheluting solvents of hexane/ethyl acetate=5/1 to give 83 mg of thedesired substance (yield: 75%).

[0196] IR(KBr) λ_(max)(cm⁻¹): 3455, 2962, 2933, 1743, 1458, 1387, 1338,1309, 1252, 1203, 1161, 1124, 1084, 1055, 984

[0197]¹H NMR (270 MHz, CDCl₃, partial data) δ (ppm): 5.67 (4H, m), 5.50(1H, dd, J=2.3, 9.9 Hz), 5.47 (1H, br.d, J=1.7 Hz), 5.30 (1H, d, J=3.0Hz), 5.12 (1H, m), 4.93 (1H, m), 4.79 (1H, d, J=3.3 Hz), 4.66 (1H, d,J=14.4 Hz), 4.55 (1H, d, J=14.4 Hz), 4.36 (1H, m), 4.05 (1H, m), 3.96(1H, br.s), 3.81 (1H, d, J=5.3 Hz), 3.40 (6H, s), 3.24 (3H, m), 3.21(1H, t, J=9.1 Hz), 2.86 (1H, t, J=9.1 Hz), 2.57 (1H, m), 1.76 (3H, s),1.28 (3H, d, J=5.9 Hz), 1.23 (3H, d, J=5.9 Hz), 1.16 (3H, d, J=6.9 Hz),0.91 (9H, s), 0.12 (15H, s)

[0198]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 170.4, 140.4, 136.7, 135.8,135.1, 134.4, 130.0, 125.0, 120.7, 120.5, 118.5, 98.3, 95.7, 94.9, 84.7,83.8, 81.7, 80.7, 80.6, 79.1, 78.3, 74.7, 73.3, 69.5, 68.3, 68.0, 67.5(*2), 67.1, 56.9, 56.4, 47.2, 40.9, 39.7, 36.1, 35.2, 35.1, 34.4, 34.2,30.4, 27.4, 25.8 (*3), 20.1, 20.0, 18.4 (*2), 18.0, 16.4, 15.0, 12.9,12.0, 3.7, 2.4 (*3), −4.5, −4.8

EXAMPLE 25 Preparation of Compound 25

[0199] Compound 24 (87 mg) was dissolved in tetrahydrofuran (0.10 mL),Solution A (0.10 mL) was added to the solution, and the mixture wasstirred overnight at room temperature. Then, the reaction mixture wastreated and purified in the manners similar to those in Example 2 togive 0.74 g of the desired compound (yield: 100%).

[0200] HR-FAB-MS: calcd for C₅₀H₇₅O₁₄I [M+Na]⁺ 1049.4099 found 1049.4099

[0201] IR(KBr) λ_(max)(cm⁻¹): 3462, 2966, 2933, 1714, 1454, 1380, 1340,1300, 1263, 1194, 1161, 1120, 1053, 985

[0202]¹H NMR (270 MHz, CDCl₃, partial data) δ (ppm): 5.84 (1H, m), 5.73(3H, m), 5.53 (1H, dd, J=2.0, 9.7 Hz), 5.40 (1H, br.s), 5.35 (1H, m),5.31 (1H, d, J=3.3 Hz), 4.97 (1H, m), 4.75 (1H, d, J=3.3 Hz), 4.66 (2H,s), 4.27 (1H, m), 4.05 (1H, m), 3.94 (1H, d, J=6.3 Hz), 3.91 (1H, br.s),3.41 (6H, s), 3.27 (1H, d, J=2.3 Hz), 3.23 (2H, m), 3.18 (1H, t, J=8.9Hz), 2.86 (1H, t, J=8.9 Hz), 2.50 (1H, m), 2.00 (1H, m), 1.85 (3H, s),1.76 (1H, m), 1.47 (3H, s), 1.27 (3H, d, J=6.3 Hz), 1.22 (3H, d, J=6.3Hz), 1.14 (3H, d, J=6.6 Hz)

[0203]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 173.6, 139.5, 138.0, 137.9,136.2, 135.1, 127.7, 124.7, 120.3, 118.2, 117.9, 98.3, 95.7, 94.8, 84.6,81.8, 80.7, 80.3, 79.2, 79.0, 78.2, 74.8, 73.2, 68.3 (*3), 67.6, 67.4,67.1, 56.9, 56.5, 45.6, 40.4, 39.7, 36.5, 35.1 (*2), 34.4, 34.2, 30.5,27.4, 20.1, 19.9, 18.3, 18.0, 16.3, 15.0, 12.9, 12.0, 3.7

EXAMPLE 26 Preparation of Compound 26

[0204] Compound 21 (80 mg) was dissolved in dichloromethane (0.90 mL),acetic anhydride (86 μl) was added to the solution, and the mixture wasstirred at room temperature for 3 hours. A saturated aqueous sodiumhydrogencarbonate solution was added to the mixture, and then themixture was extracted with dichloromethane. The collecteddichloromethane layer was washed with saturated brine and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure to give a crude product.

[0205] The resulting crude product was dissolved in tetrahydrofuran(0.10 mL), Solution A (0.10 mL) was added to the solution, and themixture was stirred overnight at room temperature. Then, the mixture wastreated in the manner similar to that in Example 2. The resultingproduct was purified by column chromatography on silica gel with elutingsolvents of chloroform/methanol=50/1 to give 46 mg of the desiredcompound (yield: 66%).

[0206] HR-FAB-MS: calcd for C₅₂H₇₉O₁₅N [M+Na]⁺ 980.5347 found 980.5342

[0207] IR(KBr) λ_(max)(cm⁻¹): 3455, 2968, 2933, 1724, 1716, 1660, 1549,1454, 1381, 1340, 1290, 1194, 1161, 1120, 1053, 987

[0208]¹H NMR (270 MHz, CDCl₃, partial data) δ (ppm): 6.74 (1H, br.s),5.82 (1H, m), 5.73 (3H, m), 5.53 (1H, dd, J=2.3, 9.7 Hz), 5.40 (1H,br.s), 5.38 (1H, m), 5.35 (1H, d, J=3.3 Hz), 4.95 (1H, m), 4.74 (1H, d,J=3.3 Hz), 4.66 (2H, s), 4.26 (1H, m), 3.94 (1H, d, J=6.3 Hz), 3.91 (1H,br.s), 3.42 (6H, s), 3.27 (1H, d, J=2.0 Hz), 3.20 (1H, t, J=9.1 Hz),2.87 (1H, t, J=9.2 Hz), 2.50 (1H, m), 2.00 (1H, m), 1.97 (3H, s), 1.85(3H, s), 1.73 (1H, m), 1.47 (3H, s), 1.23 (3H, d, J=5.9 Hz), 1.21 (3H,d, J=5.6 Hz), 1.13 (3H, d, J=6.9 Hz)

[0209]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 173.7, 170.0, 139.6, 137.9(*2), 136.2, 135.1, 127.7, 124.7, 120.3, 118.2, 117.9, 98.1, 95.7, 94.9,85.3, 81.9, 80.4, 80.3, 79.3, 79.1, 77.9, 74.8, 72.0, 68.4, 68.3 (*2),67.8, 67.6, 67.1, 56.4, 56.2, 45.6, 40.4, 40.2, 39.7, 36.6, 35.1, 34.8,34.4, 34.2, 30.5, 27.4, 23.1, 20.1, 19.9, 18.3, 17.9, 16.3, 15.1, 12.9,12.0

EXAMPLE 27 Preparation of Compound 27

[0210] Compound 23 (50 mg) was dissolved in dimethyl sulfoxide (0.50mL), piperidine (11 μl) was added to the solution, and the mixture wasstirred at 40° C. for 1 hour. Purified water was added to the mixture,and then the mixture was extracted with ethyl acetate. The collectedethyl acetate layer was washed with water and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure togive a crude product. The resulting crude product was purified by columnchromatography on silica gel with eluting solvents ofchloroform/methanol=30/1 to give 37 mg of the desired substance (yield:73%). As chloroform for the eluting solvent, ten drops of 30% aqueousammonia was added dropwise to 100 mL of chloroform and used.

[0211] HR-FAB-MS: calcd for C₅₄H₈₅O₁₄N₂ [M+H]⁺ 984.6048 found 984.6053

[0212] IR(KBr) λ_(max)(cm⁻¹): 3450, 2966, 2933, 1736, 1718, 1452, 1383,1342, 1309, 1271, 1196, 1161, 1122, 1053, 985

[0213]¹H NMR (270 MHz, CDCl₃, partial data) δ (ppm): 5.85 (1H, m), 5.73(3H, m), 5.53 (1H, dd, J=2.0, 9.9 Hz), 5.40 (1H, br.s), 5.38 (1H, m),5.29 (1H, d, J=3.0 Hz), 4.96 (1H, m), 4.75 (1H, d, J=3.3 Hz), 4.67 (2H,s), 4.27 (1H, br.d, J=5.7 Hz), 4.01 (1H, br.s), 3.95 (1H, d, J=5.9 Hz),3.42 (6H, s), 3.28 (1H, d, J=2.0 Hz), 3.18 (1H, t, J=8.9 Hz), 2.82 (1H,t, J=8.9 Hz), 2.60 (2H, t, J=5.9 Hz), 2.50 (5H, m), 2.00 (1H, m), 1.85(3H, s), 1.76 (1H, m), 1.47 (3H, s), 1.23 (3H, d, J=5.6 Hz), 1.21 (3H,d, J=5.3 Hz), 1.14 (3H, d, J=6.9 Hz)

[0214]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 173.6, 139.6, 138.0, 137.9,136.2, 135.1, 127.7, 124.7, 120.3, 118.2, 118.0, 98.5, 95.7, 94.9, 84.9,81.8, 80.8, 80.3, 79.2, 79.1, 78.2, 74.8, 69.8, 68.4, 68.3 (*2), 67.7,67.6, 67.2, 58.7, 57.1, 56.6, 54.6 (*2), 45.7, 40.4, 39.7, 36.6, 35.3,35.1, 34.4, 34.2, 30.5, 27.5, 25.4 (*2), 24.0, 20.1, 19.9, 18.3, 17.9,16.3, 15.0, 12.9, 12.0

Example 28 Preparation of Compound 28

[0215] Compound 23 (50 mg) was dissolved in dimethyl sulfoxide (0.50mL), morpholine (5.0 μl) was added to the solution, and the mixture wasstirred at 40° C. for 2 hours. Purified water was added to the mixture,and then the mixture was extracted with ethyl acetate. The collectedethyl acetate layer was washed with water and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure togive a crude product. The resulting crude product was purified by columnchromatography on silica gel with eluting solvents ofchloroform/methanol=30/1 to give 50 mg of the desired substance (yield:100%). As chloroform for the eluting solvent, ten drops of 30% aqueousammonia was added dropwise to 100 mL of chloroform and used.

[0216] HR-FAB-MS: calcd for C₅₄H₈₄O₁₅N [M]⁺ 986.5841 found 986.5848

[0217] IR(KBr) λ_(max)(cm⁻¹): 3469, 2966, 2933, 1736, 1452, 1381, 1340,1309, 1248, 1159, 1122, 1053, 985

[0218]¹H NMR (270 MHz, CDCl₃, partial data) δ (ppm): 5.84 (1H, m), 5.73(3H, m), 5.52 (1H, dd, J=2.3, 9.9 Hz), 5.40 (1H, br.s), 5.37 (1H, m),5.29 (1H, d, J=3.3 Hz), 4.97 (1H, m), 4.74 (1H, d, J=3.3 Hz), 4.66 (2H,s), 4.27 (1H, br.s), 4.01 (1H, s), 3.98 (1H, d, J=6.3 Hz), 3.91 (1H,br.s), 3.75 (4H, br.s), 3.41 (6H, s), 3.27 (1H, d, J=1.9 Hz), 3.18 (1H,t, J=8.9 Hz), 2.81 (1H, t, J=9.1 Hz), 2.63 (2H, br.s), 2.59 (4H, br.s),2.18 (1H, m), 2.00 (1H, m), 1.85 (3H, s), 1.76 (1H, m), 1.47 (3H, s),1.23 (3H, d, J=5.6 Hz), 1.21 (3H, d, J=5.6 Hz), 1.14 (3H, d, J=6.9 Hz)

[0219]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 173.6, 139.6, 138.0, 137.9,136.2, 135.1, 127.7, 124.7, 120.3, 118.2, 118.0, 98.4, 95.7, 94.8, 84.9,81.8, 80.9, 80.3, 79.2, 79.1, 78.2, 74.8, 68.4, 68.3 (*3), 67.6, 67.5,67.2, 66.5 (*2), 58.5, 56.9, 56.6, 53.6 (*2), 45.6, 40.4, 39.7, 36.6,35.2, 35.1, 34.4, 34.2, 30.5, 27.4, 20.1, 19.9, 18.3, 17.8, 16.3, 15.0,12.9, 12.0

EXAMPLE 29 Preparation of Compound 29

[0220] Compound 23 (50 mg) was dissolved in dimethyl sulfoxide (0.50mL), piperazine (5.2 mg) was added to the solution, and the mixture wasstirred at 40° C. for 2 hours. Purified water was added to the mixture,and then the mixture was extracted with ethyl acetate. The collectedethyl acetate layer was washed with water and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure togive a crude product. The resulting crude product was purified by columnchromatography on silica gel with eluting solvents ofchloroform/methanol 30/1 to give 39 mg of the desired substance (yield:78%). As chloroform for the eluting solvent, ten drops of 30% aqueousammonia was added dropwise to 100 mL of chloroform and used.

[0221] HR-FAB-MS: calcd for C₅₄H₈₅O₁₄N₂ [M+H]⁺ 985.6001 found 985.6019

[0222] IR(KBr) λ_(max)(cm⁻¹): 3452, 2966, 2933, 1738, 1716, 1454, 1385,1342, 1309, 1263, 1193, 1159, 1122, 1053, 985

[0223]¹H NMR (270 MHz, CDCl₃, partial data) δ (ppm): 5.84 (1H, m), 5.73(3H, m), 5.53 (1H, dd, J=2.3, 9.9 Hz), 5.39 (1H, br.s), 5.36 (1H, m),5.28 (1H, d, J=3.0 Hz), 4.96 (1H, m), 4.75 (1H, d, J=3.0 Hz), 4.66 (2H,s), 4.27 (1H, br.d, J=6.0 Hz), 3.95 (1H, br.s), 3.92 (1H, d, J=6.0 Hz),3.41 (6H, s), 3.27 (1H, d, J=2.9 Hz), 3.18 (1H, t, J=8.9 Hz), 2.93 (4H,br.s), 2.80 (1H, t, J=8.9 Hz), 2.56 (7H, m), 2.00 (1H, m), 1.85 (3H, s),1.76 (1H, m), 1.47 (3H, s), 1.22 (3H, d, J=5.6 Hz), 1.21 (3H, d, J=5.9Hz), 1.14 (3H, d, J=6.9 Hz)

[0224]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 173.6, 139.6, 138.0, 137.9,136.2, 135.1, 127.7, 124.7, 120.3, 118.2, 118.0, 98.5, 95.7, 94.8, 84.9,81.8, 80.9, 80.3, 79.2, 79.1, 78.3, 74.8, 69.9, 68.3 (*2), 67.6, 67.5,67.4, 67.2, 58.6, 57.1, 56.6, 53.7 (*2), 45.7, 45.3 (*2), 40.4, 39.7,36.5, 35.3, 35.1, 34.4, 34.2, 30.5, 27.4, 20.1, 19.9, 18.3, 17.8, 16.3,15.0, 12.9, 12.0

EXAMPLE 30 Preparation of Compound 30

[0225] 5-O-tert-Butyldimethylsilyl-7-O-trimethylsilylayermectin B1a(0.50 g) was dissolved in dichloromethane (4.0 ml), rhodium(II)diacetate (2.0 mg) was added to the solution, then a solution of diethyldiazomalonate (0.44 g) in dichloromethane (1.0 mL) prepared in themanner similar to that of the preparation of the solution of ethyldiazoacetate in dichloromethane used in Example 1 was slowly addeddropwise to the mixture, and the mixture was stirred at room temperaturefor 3 hours. A saturated aqueous sodium hydrogencarbonate solution wasadded to the mixture, and then the mixture was extracted withdichloromethane. The collected dichloromethane layer was washed withsaturated brine and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure to give a crude product. The resultingcrude product was purified by column chromatography on silica gel usingstepwise elution with eluting solvents of hexane/ethyl acetate=10/1 and5/1 to give 0.20 g of the desired substance (yield: 34%).

[0226] HR-FAB-MS: calcd for C64H₁₀₄O₁₈Si₂ [M+Na]⁺ 1239.6659 found1239.6641

[0227] IR(KBr) λ_(max)(cm⁻¹): 3469, 2962, 2933, 1768, 1743, 1464, 1387,1336, 1308, 1252, 1205, 1161, 1126, 1053, 985

[0228]¹H NMR (270 MHz, CDCl₃, partial data) δ (ppm): 5.76 (3H, m), 5.64(1H, dt, J=9.2, 14.2 Hz), 5.51 (1H, dd, J=2.3, 10.2 Hz), 5.48 (1H, br.d,J=1.7 Hz), 5.29 (1H, d, J=3.3 Hz), 5.10 (1H, m), 4.94 (1H, m), 4.88 (1H,s), 4.80 (1H, d, J=3.3 Hz), 4.67 (1H, d, J=15.0 Hz), 4.56 (1H, d, J=15.0Hz), 4.38 (1H, m), 4.26 (4H, m), 3.97 (1H, br.s), 3.82 (1H, d, J=5.3Hz), 3.41 (3H, s), 3.27 (1H, d, J=2.6 Hz), 3.25 (3H, s), 3.21 (1H, t,J=8.9 Hz), 3.06 (1H, t, J=8.9 Hz), 2.58 (1H, m), 1.77 (3H, s), 1.51 (3H,s), 1.28 (12H, m), 1.18 (3H, d, J=6.9 Hz), 0.93 (9H, s), 0.13 (15H, s)

[0229]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 170.5, 167.2, 167.0, 140.4,136.7, 135.9, 135.2, 134.4, 128.0, 125.0, 120.8, 120.6, 118.5, 98.5,95.8, 94.8, 85.7, 83.8, 81.6, 81.3, 80.8, 80.7, 79.1, 78.2, 74.8, 69.5,68.3, 68.0, 67.5, 67.0 (*2), 61.8, 61.5, 56.4, 55.4, 47.2, 40.9, 39.8,36.2, 35.3, 34.5, 34.4, 34.3, 30.5, 27.5, 25.9 (*3), 20.2, 20.1, 18.4(*2), 17.8, 16.4, 15.0, 14.1, 14.0, 12.1, 2.4 (*3), −4.5, −4.8

EXAMPLE 31 Preparation of Compound 31

[0230] Compound 30 (0.10 g) was dissolved in tetrahydrofuran (1.0 mL),Solution A (0.10 mL) was added to the solution, and the mixture wasstirred at room temperature for 3 hours. Then, the reaction mixture wastreated and purified in the manners similar to those in Example 2 togive 0.46 g of the desired compound (yield: 54%).

[0231] HR-FAB-MS: calcd for C₅₀H₇₅O₁₄I [M+Na]⁺ 1049.4099 found 1049.4099

[0232] IR(KBr) λ_(max)(cm⁻¹): 3462, 2966, 2933, 1714, 1454, 1380, 1340,1300, 1263, 1194, 1161, 1120, 1053, 985

[0233]¹H NMR (270 MHz, CDCl₃, partial data) δ (ppm): 5.85 (1H, m), 5.74(3H, m), 5.54 (1H, dd, J=2.3, 9.9 Hz), 5.41 (1H, br.s), 5.39 (1H, m),5.31 (1H, d, J=3.3 Hz), 4.97 (1H, m), 4.88 (1H, s), 4.76 (1H, d, J=3.3Hz), 4.68 (2H, s), 4.26 (5H, m), 3.96 (1H, d, J=6.3 Hz), 3.93 (1H,br.s), 3.42 (3H, s), 3.28 (1H, d, J=2.0 Hz), 3.26 (3H, s), 3.18 (1H, t,J=8.9 Hz), 3.06 (1H, t, J=9.1 Hz), 2.52 (1H, m), 2.01 (1H, m), 1.86 (3H,s), 1.77 (1H, m), 1.48 (3H, s), 1.27 (12H, m), 1.16 (3H, d, J=6.9 Hz)

[0234]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 173.7, 167.1, 167.0, 139.6,138.1, 138.0, 136.2, 135.1, 127.8, 124.7, 120.4, 118.3, 118.0, 98.5,95.8, 94.7, 85.7, 81.7, 81.2, 80.8, 80.4, 79.3, 79.1, 78.2, 74.9, 68.4,68.3 (*2), 67.7, 67.2, 66.8, 61.8, 61.5, 56.5, 55.5, 45.7, 40.5, 39.8,36.6, 35.1, 34.5, 34.4, 34.2, 30.5, 27.5, 20.2, 19.9, 18.4, 17.8, 16.4,15.1, 14.1, 14.0, 12.9, 12.0

EXAMPLE 32 Preparation of Compound 35

[0235] Under nitrogen atmosphere,5-O-tert-butyldimethylsilyl-7-O-trimethylsilylivermectin (0.10 g)obtained in Reference Example 3 was dissolved in dichloromethane (0.20mL), diacetylrhodium dimer (1.0 mg) was added to the solution, and themixture was stirred at room temperature for 10 minutes. Then, a solutionof ethyl diazoacetate (22 μl) in dichloromethane (0.20 mL) was slowlyadded dropwise to the mixture, and the mixture was stirred at roomtemperature for 5.5 hours. A saturated aqueous sodium hydrogencarbonatesolution was added to the mixture, and then the mixture was extractedwith dichloromethane. The collected dichloromethane layer was washedwith saturated brine and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure to give a crude product.The resulting crude product was is purified by column chromatography onsilica gel using stepwise elution with eluting solvents of hexane/ethylacetate=5/1 and 2/1 to give 0.59 g of the desired substance (yield:55%).

[0236] IR(KBr) λ_(max)(cm⁻¹): 3450, 2960, 2933, 1743, 1456, 1387, 1338,1308, 1252, 1201, 1169, 1128, 1101, 1055, 985

[0237]¹H NMR (270 MHz, CDCl₃, partial data) δ (ppm): 5.70 (3H, m), 5.47(1H, br.s), 5.30 (1H, d, J=2.6 Hz), 5.12 (1H, m), 4.86 (1H, m), 4.81(1H, d, J=3.0 Hz), 4.66 (1H, d, J=14.2 Hz), 4.56 (1H, d, J=14.2 Hz),4.36 (1H, m), 4.36 (1H, d, J=3.6 Hz), 4.21 (2H, q, J=7.1 Hz), 3.97 (1H,br.s), 3.81 (1H, d, J=5.3 Hz), 3.40 (3H, s), 3.35 (3H, s), 3.24 (1H, m),3.21 (1H, t, J=8.6 Hz), 2.95 (1H, t, J=8.9 Hz), 2.58 (1H, m), 2.29 (5H,m), 1.77 (3H, s), 1.51 (3H, s), 1.31 (3H, d, J=5.9 Hz), 1.28 (3H, t,J=7.1 Hz), 1.27 (3H, d, J=6.9 Hz), 1.17 (3H, d, J=6.9 Hz), 0.93 (9H, s),0.13 (15H, s)

[0238]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 170.7, 170.5, 140.4, 136.8,135.1, 134.3, 124.9, 120.8, 120.5, 118.8, 98.3, 97.5, 94.8, 84.8, 83.6,81.5, 80.9, 80.7, 79.1, 78.7, 70.0, 69.5, 68.8, 67.4, 67.3, 67.2, 67.1,60.6, 56.3, 56.2, 47.2, 41.8, 39.6, 36.4, 35.6, 35.5, 34.8, 34.3, 34.1,31.2, 28.0, 27.1, 25.8 (*3), 20.1, 20.0, 18.4 (*2), 17.9, 17.4, 15.0,14.2, 12.3, 11.9, 2.3 (*3), −4.5, −4.7

EXAMPLE 33 Preparation of Compound 36

[0239] Compound 35 (50 mg) was dissolved in tetrahydrofuran (500 μl),Solution A (50 μl) was added to the solution, and the mixture wasstirred overnight at room temperature. Then, the reaction mixture wastreated and purified in the manners similar to those in Example 2 togive 47 mg of the desired compound (yield: 100%).

[0240] HR-FAB-MS: calcd for C₅₂H₈₀O₁₆ [M+Na]⁺ 983.5344 found 983.5338

[0241] IR(KBr) λ max(cm⁻¹): 3481, 2964, 2931, 1758, 1737, 1456, 1379,1340, 1300, 1273, 1198, 1172, 1122, 1101, 1053, 987

[0242]¹H NMR (270 MHz, CDCl₃, partial data) δ (ppm): 5.86 (1H, m), 5.75(2H, m), 5.42 (1H, br.s), 5.35 (1H, m), 5.32 (1H, d, J=3.3 Hz), 4.97(1H, m), 4.77 (1H, d, J=3.0 Hz), 4.68 (2H, br.s), 4.37 (1H, d, J=4.0Hz), 4.29 (1H, m), 4.21 (2H, q, J=7.1 Hz), 4.11 (1H, br.s), 3.97 (1H, d,J=6.3 Hz), 3.93 (1H, br.s), 3.81 (2H, m), 3.64 (3H, m), 3.42 (3H, s),3.36 (3H, s), 3.28 (1H, q, J=2.3 Hz), 3.20 (1H, t, J=9.0 Hz), 2.95 (1H,t, J=8.9 Hz), 2.52 (1H, m), 2.26 (5H, m), 1.97 (1H, m), 1.87 (3H, s),1.49 (3H, s), 1.31 (3H, d, J=5.9 Hz), 1.28 (3H, t, J=7.1 Hz), 1.24 (3H,d, J=6.3 Hz), 1.13 (3H, d, J=6.9 Hz)

[0243]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 173.8, 170.5, 139.6, 138.0,137.9, 134.9, 124.6, 120.4, 120.0, 118.0, 98.3, 97.4, 94.6, 84.7, 81.6,80.8, 80.3, 79.2, 79.0, 78.5, 76.6, 70.0 (β2), 68.6, 68.4, 67.6, 67.1(*2), 60.6, 56.5, 56.2, 45.6, 41.1, 39.7, 36.9, 35.7, 35.4, 34.8, 34.4,34.0, 31.2, 28.0, 27.2, 20.2, 19.9, 18.3, 17.9, 17.4, 15.1, 14.2, 12.4,12.0

EXAMPLE 34 Preparation of Compound 39

[0244] Compound 35 (500 mg, 436 mmol) was dissolved in tetrahydrofuran(4.5 mL), a 1 mol/L aqueous potassium hydroxide solution (650 μL) wasadded to the solution, and the mixture was stirred at room temperaturefor 18 hours. A saturated aqueous ammonium chloride solution (5 mL) wasadded to the mixture for neutralization, and the mixture was extracted 3times with ethyl acetate (5 mL). The collected ethyl acetate layers werewashed with a saturated aqueous ammonium chloride solution (5 mL) andsaturated brine (5 mL) and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure to give a crude product.The crude product was treated and purified in the manners similar tothose in Example 2 to give 198 mg of the desired compound (yield: 49%,for the two steps).

[0245] HR-FAB-MS: calcd for C₅₀H₇₅O₁₆ [M+2Na]⁺ 977.4851 found 977.4877IR(KBr) λ_(max)(cm⁻¹): 3465, 2966, 2933, 1763, 1735, 1456, 1379, 1342,1309, 1273, 1244, 1200, 1171, 1122, 1055, 985

EXAMPLE 35 Preparation of Compound 37

[0246] Under nitrogen atmosphere, a 1.0 mol/L solution of super hydridein tetrahydrofuran (12.6 mL, 12.9 mmol) was added dropwise to a solutionof Compound 35 (2.48 g, 2.16 mmol) in tetrahydrofuran (21 mL) at −78°C., and the mixture was stirred at the same temperature for 2 hours.After a 30% aqueous hydrogen peroxide solution (1.6 mL) was added to themixture, the mixture was stirred at the same temperature for 30 minutes.Sodium sulfite (100 mg) was added to the mixture, and the mixture wasextracted 3 times with ethyl acetate (30 mL). The collected ethylacetate layers were washed with saturated brine (10 mL) and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure to give a crude product. The resulting crude product waspurified by chromatography on silica gel (150 g) with eluting solventsof hexane/ethyl acetate=3/1 to give 1.59 g of the desired compound(yield: 67%).

[0247] HR-FAB-MS: calcd for C61H₁₀₂O₁₆Si₂ [M+Na]⁺1127.6498, found1127.6484

[0248] IR(KBr) λ_(max)(cm⁻¹): 3461, 2960, 2931, 1743, 1461, 1387, 1336,1309, 1252, 1203, 1168, 1124, 1105, 1055, 1009, 985

EXAMPLE 36 Preparation of Compound 40

[0249] Compound 37 (90.0 mg, 81.4 μmol) was treated and purified in themanners similar to those in Example 2 to give 65.7 mg of the desiredcompound (yield: 88%). HR-FAB-MS: calcd for C₅₀H₇₈O₁₅ [M+Na]⁺ 941.5238,found 941.5229 IR(KBr) λ_(max)(cm⁻¹): 3459, 2964, 2933, 1738, 1456,1379, 1340, 1308, 1245, 1198, 1171, 1120, 1054, 1011, 985

EXAMPLE 37 Preparation of Compound 38

[0250] Under nitrogen atmosphere, triphenylphosphine (473 mg, 1.79mmol), imidazole (491 mg, 7.19 mmol) and carbon tetrabromide (598 mg,1.79 mmol) were added to a solution of Compound 37 (795 mg, 719 u mol)in dichloromethane (7.2 mL), and the mixture was stirred at roomtemperature for 2 hours. After a 30% aqueous hydrogen peroxide solution(1.6 mL) was added to the mixture, the mixture was stirred for 30minutes at the same temperature. Sodium sulfite (100 mg) was added tothe mixture, and the mixture was extracted 3 times with ethyl acetate(30 mL). The collected ethyl acetate layers were washed with saturatedbrine (10 mL) and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure to give a crude product. The resultingcrude product was purified by chromatography on silica gel (150 g) witheluting solvents of hexane/ethyl acetate=5/1 to give 432 mg of thedesired compound (yield: 51%).

[0251] HR-FAB-MS: calcd for C₅₉H₉₉BrO₁₄Si₂ [M+Na]⁺ 1189.5654, found1189.5674

[0252] IR(KBr) λ_(max)(cm⁻¹): 2960, 2931, 1743, 1461, 1387, 1336, 1309,1252, 1203, 1168, 1124, 1105, 1055, 1009, 985

EXAMPLE 38 Preparation of Compound 41

[0253] Compound 38 (126 mg, 107 μmol) was treated and purified in themanners similar to those in Example 2 to give 67.2 mg of the desiredcompound (yield: 64%). HR-FAB-MS: calcd for C₅₀H₇₇BrO₁₄ [M+Na]⁺1003.4394, found 1003.4411

[0254] IR(KBr) λ_(max)(cm⁻¹): 3455, 2964, 2931, 1731, 1717, 1456, 1379,1340, 1308, 1274, 1243, 1196, 1171, 1120, 1053, 985

EXAMPLE 39 Preparation of Compound 42

[0255] Reactions were performed, and the product was treated andpurified in the manners similar to those in Example 1 by using5-O-tert-butyldimethylsilyl-7-O-trimethylsilylayermectin B2a (100 mg,92.8 μmol) obtained in Reference Example 5 to give 32.3 mg of thedesired compound (yield: 30%).

[0256] IR(KBr) λ_(max)(cm⁻¹): 3531, 2962, 2933, 1743, 1462, 1387, 1336,1296, 1252, 1203, 1167, 1126, 1099, 1053, 984

EXAMPLE 40 Preparation of Compound 43

[0257] Compound 42 (32.3 mg, 27.3 μmol) was treated and purified in themanners similar to those in Example 2 to give 19.1 mg of the desiredcompound (yield: 70%).

[0258] HR-FAB-MS: calcd for C₅₂H₈₀O₁₇ [M+Na]⁺ 999.5293, found 999.5289

[0259] IR(KBr) λ_(max)(cm⁻¹): 3525, 2967, 2933, 1759, 1737, 1452, 1387,1340, 1300, 1263, 1198, 1169, 1124, 1084, 1053, 985

EXAMPLE 41 Preparation of Compound 44

[0260] Under nitrogen atmosphere, dimethyl sulfoxide (30 μl) was addedto a solution of oxalyl chloride (20 μl, 214 μmol) in dichloromethane(200 μl) at −78° C., and the mixture was stirred for 5 minutes. Then,Compound 42 (50.0 mg, 42.9 μmol) and a solution of triethylamine (60 μl)in dichloromethane (700 μl) were added dropwise to the mixture, and themixture was warmed to 0° C. and further stirred for 3 hours. After asaturated aqueous ammonium chloride solution (5 mL) was added to thereaction solution, the mixture was extracted 3 times withdichloromethane (10 mL), and the organic layer was dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure togive a crude product. The resulting crude product was purified bychromatography on silica gel (250 mg) with eluting solvents ofhexane/ethyl acetate=3/1 to give 41.5 mg of the desired compound (yield:83%).

[0261] HR-FAB-MS: calcd for C₈₁H₁₀₀O₁₇Si₂ [M+Na]⁺ 1183.6397, found1183.6405

[0262] IR(KBr) λ_(max)(cm⁻¹): 3450, 2962, 2935, 1743, 1726, 1456, 1387,1335, 1296, 1252, 1200, 1167, 1128, 1099, 1062, 985

EXAMPLE 42 Preparation of Compound 45

[0263] Compound 44 (41.5 mg, 35.7 μmol) was treated and purified in themanners similar to those in Example to give 31.5 mg of the desiredcompound (yield: 91%).

[0264] HR-FAB-MS: calcd for C₅₂H₇₈O₁₇ [M+Na]⁺997.5137, found 997.5148

[0265] IR(KBr) λ_(max)(cm⁻¹): 3483, 2975, 2935, 1757, 1724, 1452, 1385,1340, 1298, 1238, 1200, 1169, 1124, 1101, 1055, 985

EXAMPLE 43 Preparation of Compound 46

[0266] To a solution of Compound 44 (50.3 mg, 43.3 μmol) in a mixedsolvent of methanol (1 mL) and purified water (140 μl), sodium acetate(14.2 mg, 173 u mol) and O-methylhydroxylamine hydrochloride (7.2 mg,86.6 μmol) were added, and the mixture was stirred at room temperaturefor 3 hours. After a saturated aqueous sodium hydrogencarbonate solution(5 mL) was added to the reaction solution, the mixture was extractedwith ethyl acetate (10 mL×3), and the organic layer was dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure to give a crude product. The resulting crude product waspurified by chromatography on silica gel (250 mg) with eluting solventsof chloroform/methanol=10/1 to give 48.1 mg of the desired compound(yield: 93%).

[0267] IR(KBr) λ_(max)(cm⁻¹): 3465, 2960, 2935, 1743, 1463, 1387, 1336,1296, 1252, 1203, 1169, 1128, 1099, 1053, 991

EXAMPLE 44 Preparation of Compound 47

[0268] Compound 46 (48.1 mg, 40.3 u mol) was treated and purified in themanners similar to those in Example 2 to give 40.5 mg of the desiredcompound (yield: 100%).

[0269] HR-FAB-MS: calcd for C53H81O₁₇ [M+Na]⁺ 1026.5402, found 1026.5430

[0270] IR(KBr) λ_(max)(cm⁻¹): 3483, 2972, 2935, 1759, 1735, 1452, 1383,1340, 1298, 1198, 1173, 1124, 1101, 1051, 989

REFERENCE EXAMPLE 1

[0271] 5-O-tert-Butyldimethylsilyl-7-O-trimethylsilylayermectin B1a

[0272] 5-O-tert-Butyldimethylsilylayermectin B1a (4.9 g), which wasknown from literature (Journal of Medicinal Chemistry (J. Med. Chem.),vol. 25, 658-663 (1982), was dissolved in N,N-dimethylformamide (35 mL).Imidazole (2.4 mg) and trimethylsilyl chloride (2.2 mL) were added tothe solution, and the mixture was stirred at room temperature for 6.5hours. After purified water was added, the mixture was extracted withdiethyl ether. The collected diethyl ether layer was washed with waterand dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure to give a crude product. Then, the crude productwas dissolved in tetrahydrofuran (110 mL), an aqueous acetic acidsolution (acetic acid: 44 mL, purified water: 22 mL) was slowly addeddropwise to the mixture, and the mixture was stirred at room temperaturefor 2.5 hours. A saturated aqueous sodium hydrogencarbonate solution wasadded to the mixture for neutralization, and then the mixture wasextracted with ethyl acetate. The collected ethyl acetate layer waswashed successively with a saturated aqueous sodium hydrogencarbonatesolution and saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure to give a crudeproduct. The resulting crude product was purified by columnchromatography on silica gel using stepwise elution with elutingsolvents of hexane/ethyl acetate=2/1 and 1/1 to give 3.9 g of thedesired substance (yield: 75%).

[0273]¹H NMR (270 MHz, CDCl₃, partial data) 6 (ppm): 5.73 (3H, m), 5.63(1H, dt, J=9.2, 14.2 Hz), 5.50 (1H, dd, J=2.0, 9.9 Hz), 5.48 (1H, br.s),5.36 (1H, d, J=3.3 Hz), 5.10 (1H, m), 4.93 (1H, m), 4.79 (1H, d, J=3.3Hz), 4.66 (1H, d, J=14.3 Hz), 4.55 (1H, d, J=14.3 Hz), 4.37 (1H, m),3.96 (1H, br.s), 3.81 (1H, d, J=5.6 Hz), 3.41 (3H, s), 3.39 (3H, s),3.26 (1H, d, J=2.3 Hz), 3.25 (1H, t, J=9.2 Hz), 3.15 (1H, t, J=9.2 Hz),2.57 (1H, m), 1.76 (3H, s), 1.50 (3H, s), 1.26 (3H, d, J=6.3 Hz), 1.25(3H, d, J=5.9 Hz), 1.17 (3H, d, J=6.9 Hz), 0.92 (9H, s), 0.12 (15H, s)

[0274]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 170.5, 140.4, 136.6, 135.8,135.2, 134.4, 128.0, 125.0, 120.7, 120.5, 118.5, 98.3, 95.8, 95.0, 83.6,81.7, 80.6, 80.3, 79.2, 78.1, 76.0, 74.7, 69.5, 68.3, 68.1, 68.0, 67.5,67.1, 56.3 (*2), 51.2, 47.2, 40.9, 39.7, 36.1, 35.2, 34.4, 34.2, 34.1,30.4, 27.4, 25.8 (*3), 20.1, 20.0, 18.4 (*2), 17.6, 16.4, 15.0, 12.9,12.0, 2.3 (*3), −4.5, −4.8

REFERENCE EXAMPLE 2

[0275] 5-O-tert-Butyldimethylsilylivermectin

[0276] Ivermectin (2.2 g) was dissolved in N,N-dimethylformamide (25mL), imidazole (680 mg) and tert-butyldimethylchlorosilane (750 mg) wereadded to the solution, and the mixture was stirred at room temperaturefor 3 hours. After an aqueous sodium hydrogencarbonate solution wasadded to the mixture, the mixture was extracted with The organic layerwas dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure to give a crude product. The resultingcrude product was purified by column chromatography on silica gel witheluting solvents of dichloromethane/tetrahydrofuran=20/1 to give 1.6 gof the desired substance (yield: 63%).

[0277] HR-FAB-MS: calcd for C₅₄H₈₈O₁₄Si [M+Na]⁺ 1011.5841 found1011.5873

[0278] IR(KBr) λ_(max)(cm⁻¹): 3450, 2963, 2931, 1714, 1635, 1456, 1381,1254, 1120, 987

[0279]¹H NMR (270 MHz, CDCl₃, partial data) δ (ppm): 5.80 (1H, m), 5.71(2H, m), 5.39 (1H, d, J=3.3 Hz),5.31 (2H, m),4.98 (1H, m),4.77 (1H, d,J=3.0 Hz),4.68 (1H, d, J=16.2 Hz), 4.52 (1H, d, J=16.2 Hz), 4.22 (1H,m), 3.42 (6H, s), 1.78 (3H, s), 1.50 (3H, s), 1.27 (3H, d, J=6.3 Hz),1.25 (3H, d, J=6.0 Hz), 1.15 (3H, d, J=6.9 Hz), 0.92 (9H, s), 0.13 (6H,s)

[0280]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 174.1, 141.2, 137.2 (*2),135.0, 124.8, 119.3, 118.3, 117.2, 98.5, 97.5, 94.8, 81.8, 80.4, 80.2,80.0, 79.3, 78.2, 77.5-76.5 (*1), 76.0, 69.5, 68.7, 68.1, 67.9, 67.2(*2), 56.5, 56.4, 45.7, 41.1, 39.6, 36.8, 35.7, 35.4, 34.5, 34.1 (*2),31.2, 28.1, 27.3, 25.8 (*3), 20.3, 20.0, 18.4, 17.6, 17.4, 15.2 (*2),12.4, 12.1, −4.6, −4.9

REFERENCE EXAMPLE 3

[0281] 5-O-tert-Butyldimethylsilyl-7-O-trimethylsilylivermectin

[0282] Under nitrogen atmosphere, 5-O-tert-butyldimethylsilylivermectin(8.6 g) obtained in Reference Example 2 was dissolved inN,N-dimethylformamide (87 mL). Imidazole (2.4 g) and trimethylsilylchloride (3.8 mL) were successively added to the mixture, and themixture was stirred at room temperature for 14 hours. Purified water wasadded to the mixture, and then the mixture was extracted with ethylacetate. The collected ethyl acetate layer was washed with water anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure to give a crude product. Then, the crude product wasdissolved in tetrahydrofuran (200 mL), an aqueous acetic acid solution(acetic acid: 80 mL, purified water: 40 mL) was slowly added dropwise tothe mixture, and the mixture was stirred at room temperature for 4hours. A saturated aqueous sodium hydrogencarbonate solution was addedto the mixture for neutralization, and then the mixture was extractedwith ethyl acetate. The collected ethyl acetate layer was washedsuccessively with a saturated aqueous sodium hydrogencarbonate solutionand saturated brine and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure to give a crude product.The resulting crude product was purified by column chromatography onsilica gel using stepwise elution with eluting solvents of hexane/ethylacetate=4/1 and 3/1 to give 7.7 g of the desired substance (yield: 84%).

[0283] HR-FAB-MS: calcd for C₅₇H₉₆O₁₄Si₂Na [M+Na]⁺ 1083.6236 found1083.6233

[0284] IR(KBr) λ_(max)(cm⁻¹): 3469, 2960, 2931, 1743, 1460, 1381, 1336,1308, 1252, 1203, 1168, 1120, 1083, 1052,987

[0285]¹H NMR (270 MHz, CDCl₃, partial data) δ (ppm): 5.69 (3H, m), 5.47(1H, br.s), 5.36 (1H, d, J=3.6 Hz), 5.12 (1H, m), 4.85 (1H, m), 4.80(1H, d, J=3.6 Hz), 4.66 (1H, d, J=14.2 Hz), 4.55 (1H, d, J=14.2 Hz),4.37 (1H, m), 3.97 (1H, br.s), 3.80 (1H, d, J=5.1 Hz), 3.39 (6H, s),3.20 (3H, m), 2.57 (1H, m), 2.28 (5H, m), 1.77 (3H, s), 1.50 (3H, s),1.26 (3H, d, J=6.2 Hz), 1.25 (3H, d, J=6.3 Hz), 1.17 (3H, d, J=6.6 Hz),0.97 (9H, s), 0.12 (15H, s)

[0286]¹³C NMR (67.8 MHz, CDCl₃) δ (ppm): 170.7, 140.4, 136.7, 135.1,134.3, 125.0, 120.8, 120.4, 118.8, 98.4, 97.5, 94.9, 83.6, 81.7, 80.7,80.3, 79.2, 78.2, 76.6, 76.0, 69.5, 68.8, 68.1, 67.4, 67.2, 67.1, 56.3,56.2, 47.2, 41.8, 39.6, 36.4, 35.6, 35.5, 34.4, 34.3, 34.1, 31.2, 28.1,27.1, 25.8 (*3), 20.1, 20.0, 18.4 (*2), 17.6, 17.4, 15.0, 12.3, 11.9,2.3 (*3), −4.5, −4.7

REFERENCE EXAMPLE 4

[0287] 5-O-tert-Butyldimethylsilylayermectin B2a

[0288] Avermectin B2a (3.54 g, 3.97 mmol) was used as a startingmaterial, and reactions were performed and the product was treated andpurified in the manners similar to those in Reference Example 2 to give1.90 g of the desired substance (yield: 48%).

[0289] HR-FAB-MS: calcd for C₅₄H₈₈O₁₅Si [M+Na]⁺ 1027.5790 found1027.5763

[0290] IR(KBr) λ_(max)(cm⁻¹): 3533, 2962, 2933, 1714, 1462, 1385, 1338,1304, 1255, 1196, 1167, 1124, 1082, 1051, 985

REFERENCE EXAMPLE 5

[0291] 5-O-tert-Butyldimethylsilyl-7-O-trimethylsilylayermectin B2a

[0292] 5-O-tert-Butyldimethylsilylayermectin B2a (1.00 g, 994 mmol)obtained in Reference Example 4 was used as a starting material, andreactions were performed and the product was treated and purified in themanners similar to those in Reference Example 3 to give 742 mg of thedesired substance (yield: 69%).

[0293] HR-FAB-MS: calcd for C₅₇H₉₆O₁₅Si₂ [M+Na]⁺ 1099.6185 found1099.6207

[0294] IR(KBr) λ_(max)(cm⁻¹): 3529, 2962, 2933, 1745, 1462, 1387, 1336,1304, 1252, 1187, 1169, 1126, 1084, 1053, 985

TEST EXAMPLE 1

[0295] Methods for determining antiparasitic effects of the compoundsdisclosed by the present invention are explained below.

[0296] As model insects for simple determination of antiparasitic andinsecticidal activities, those insects are desired which can be easilyobtained and bred in laboratories, and have no pathogenicity to a human.Caenorhabditis elegans, an unparasitic eelworm widely used inexperiments of genetics, was used as a typical steam worm, and artemiasalina used as feed for tropical fish and named Brine shrimp, was usedinstead of insects.

[0297] <Preparation of Caenorhabditis elegans Used for Evaluation>

[0298]Escherichia. coli for the feed of caenorhabditis elegans (mutanthaving uracil requirement) was inoculated in a seed medium for E. colito which a small amount of uracil was added, and cultured with shakingat 27° C. for 1 day. A petri dish of 6 cm diameter was filled with 10 mLof an agar medium for eelworm proliferation, and the medium wassolidified. Then 0.5 mL of the culture of E. coli was spread over themedium in the dish, and the dish was incubated at 37° C. to proliferateE. coli A piece of the agar was collected with a platinum loop from apetri dish in which caenorhabditis elegans successfully proliferated,and inoculated in petri dishes in which E. coli was proliferated. Thepetri dishes were incubated at 20° C. to proliferate caenorhabditiselegans. Since the life of eelworm is about 2 weeks, subculture wascarried out every once a week. The eelworms grown with spread on thesurface of the petri dish after 3 to 5 days from subculture were usedfor the experiments.

[0299] <Preparation of artemia salina Used for Evaluation>

[0300] To a buffer for artemia salina (obtained by dissolving 0.24% ofTris, 2.57% of sodium chloride, 0.47% of magnesium chloride, 0.07% ofpotassium chloride, 0.02% of sodium carbonate, 0.64% of magnesiumsulfate and 0.11% of calcium chloride in distilled water and adjustingthe pH to 7.1 with hydrochloric acid), dried eggs of artemia salina[Tetra Brine Shrimp Eggs, Warner Lambert Co.] were added. The nopriuslarvae 1 or 2 days after hatching were used for the experiments.

[0301] <Preparation of Agar Medium for Eelworm Proliferation>

[0302] Solution A was obtained by dissolving 0.3% of sodium chloride,1.7% of bact-agar (DIFCO Co.), 0.5% of bact-peptone (DIFCO Co.) and 1.0%of yeast extract (DIFCO Co.) in distilled water.

[0303] Solution B was obtained by dissolving 0.5% of cholesterol inethanol.

[0304] Solution C was obtained by dissolving 13.9% of calcium chloridein distilled water.

[0305] Solution D was obtained by dissolving 30.8% of magnesium sulfateheptahydrate in distilled water.

[0306] Solution E was obtained by dissolving 13.54% of KH₂PO₄ and 4.45%of K₂HPO₄ in distilled water.

[0307] The aforementioned Solutions A, C and D were sterilized in anautoclave at 121° C. for 20 minutes, and each solution was stored at 4°C.

[0308] The agar medium for eelworm proliferation was prepared by mixingthe solutions in the following proportion: Solution A: 100 mL, SolutionB: 0.1 mL, Solution C: 0.05 mL, Solution D: 0.1 mL and Solution E: 2.5mL (without pH adjustment), and dispensing each 10 mL portion into petridishes of 60×15 mm.

[0309] <Preparation of E. coli Seed Medium>

[0310] In distilled water, 2.0% of bact-trypton (DIFCO Co.), 0.55% ofsodium chloride and 0.001% of uracil (SIGMA Co., pH 7.4) were dissolved,and the solution was sterilized in an autoclave at 121° C. for 20minutes.

[0311] <Experimental Procedure>

[0312] Each well of a 96 well microplate was filled with the solution ofthe test compound (methanol as a solvent), and the solvent was removedusing a vacuum pump, then 250 μl of the assay medium was added to eachwells (the assay medium was prepared by dissolving 7.5 mM sodiumhydrogencarbonate, 7.5 mM potassium chloride, 7.5 mM calcium chloridedihydrate and 7.5 mM magnesium sulfate heptahydrate in distilled waterand adding 0.01% of lecithin to the solution), and then the microplatewas shaken using a microplate mixer for 15 minutes. To each well, a fewindividuals of caenorhabditis elegans were added by softly rubbing thesurface of the agar using a toothpick, or a few individuals of artemiasalina were added together with 50 μgl of the buffer. The microplate wasincubated at 20° C., and then the insects were observed after 24 and 48hours under a microscope (magnification of 40×). The results werecompared to those obtained without addition of the test compound, andevaluated by 4 grades.

[0313] The evaluation results were shown by indications of 4 grades from0 to 3.

[0314] 3: No movement

[0315] 2: Between 1 and 3

[0316] 1: A little week movements

[0317] 0: Active movements

[0318] Of the 4 grades, Indications 3 and 2 were judged as effective,and Indications 1 and 0 as ineffective. The results are shown in Table5. In Table 5, the values for each compound are minimum inhibitoryconcentrations (MIC) which were required to give Indication 2 (or 3) forcaenorhabditis elegans or artemia salina. In Table 5, caenorhabditiselegans and artemia salina are abbreviated as C.E. and A.S.,respectively. TABLE 5 Compound No. C.E.(ng/ml) A.S.(ng/ml) B1a* 2 0.5  22 0.5  7 0.1 0.02  9 2 2 10 0.5 0.5 12 2 0.5 36 2 0.5 39 0.5 0.1 40 20.5 43 2 0.5 45 0.5 0.5 47 2 2

INDUSTRIAL APPLICABILITY

[0319] According to the present invention, avermectin derivatives andsalts thereof having antiparasitic activity are provided. Theaforementioned derivatives and salts thereof are useful as activeingredients of antiparasitic agents.

What is claimed is:
 1. A compound represented by the general formula (I)or a salt thereof:

wherein, —X

Y— represents —CH═CH—, —CH₂—C(═O)—, —CH₂—CH₂—, —CH₂—CH(R¹³)— (whereinR¹³ represents a hydroxyl group or a lower alkylcarbonyloxy group) or—CH₂—C(═N—OR^(13c))— (wherein R^(13c) represents a hydrogen atom or alower alkyl group),

between R² and the carbon atom at 5-position represents a single bond ora double bond, R¹ represents a substituted or unsubstituted lower alkylgroup, a formyl group, a carboxyl group, a lower alkoxycarbonyl group(wherein a lower alkyl moiety of said lower alkoxycarbonyl group may besubstituted with a heterocyclic group), —CH═N—OR⁴ (wherein R⁴ representsa hydrogen atom or a lower alkyl group), a lower alkenyloxycarbonylgroup, —CH═N—NH—CONH₂, a cyano group, —COR⁵ (wherein R⁵ represents anarylalkyloxy group (wherein the aryl group may contain one or morehetero atoms as ring-constituting atoms) or —NR⁶R⁷ (wherein R⁶ and R⁷are combined together with the adjacent nitrogen atom to form anitrogen-containing heterocyclic group), a vinyl group substituted witha lower alkenyloxycarbonyl group, —CO—S—CH₂—CH₂—NH—CO—R^(x) (whereinR^(x) represents a lower alkyl group), —CH═CH—COOH, or a substituted orunsubstituted aryl group, and R^(1a) represents a hydrogen atom,provided that when R¹ represents a lower alkoxycarbonyl group (wherein alower alkyl moiety of said lower alkoxycarbonyl group may be substitutedwith a heterocyclic group) or a carboxyl group, R^(1a) may furtherrepresents a lower alkoxycarbonyl group (wherein a lower alkyl moiety ofsaid lower alkoxycarbonyl group may be substituted with a heterocyclicgroup), a carboxyl group, a cyano group, or an aryl group, and providedthat when —X

Y— is —CH₂—C(═O), —CH₂—CH₂—, or —CH₂—CH(R^(13d))— (wherein R^(13d)represents a lower alkylcarbonyloxy group), a substituent at the4″-position may be a hydroxyl group instead of OCHR¹R^(1a), when

between R² and the carbon atom at 5-position is a single bond, R²represents a hydroxyl group, a lower alkoxyl group, or a tri(loweralkyl)silyloxy group, and when

between R² and the carbon atom at the 5-position is a double bound, R²is combined with the carbon atom at 5-position to form a carbonyl groupor a hydroxime group (—C(═NOH)), and R³ represents a hydroxyl group or atri(lower alkyl)silyloxy group.
 2. The compound or a salt thereofaccording to claim 1, wherein R² is a hydroxyl group.
 3. The compound ora salt thereof according to claim 1, wherein R² is combined with thecarbon atom at 5-position to form a hydroxime group (—C(═NOH)).
 4. Thecompound or a salt thereof according to any one of claims 1 to 3,wherein R³ is a hydroxyl group.
 5. A medicament which comprises thecompound according to any one of claims 1 to 4 or a physiologicallyacceptable salt thereof as an active ingredient.
 6. An antiparasiticagent which comprises the compound according to any one of claims 1 to 4or a physiologically acceptable salt thereof as an active ingredient. 7.Use of the compound according to any one of claims 1 to 4 or aphysiologically acceptable salt thereof for manufacture of anantiparasitic agent.
 8. A method for therapeutic treatment ofparasitosis which comprises the step of administering to a mammalincluding a human a therapeutically effective amount of the compound orthe physiologically acceptable salt thereof according to any one ofclaims 1 to 4.